Inhibitors of tdp-43 and tau aggregation

Abstract

Herein, compounds, compositions and methods for modulating inclusion formation and stress granules in cells related to the onset of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections are described.

Description

[0001] INHIBITORS OF TDP-43 AND TAU AGGREGATION

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 489,407, filed March 9, 2023, the contents of which are hereby incorporated by reference.

[0004] BACKGROUND

[0005] One of the hallmarks of many neurodegenerative diseases is the accumulation of protein inclusions in the brain and central nervous system. These inclusions are insoluble aggregates of proteins and other cellular components that cause damage to cells and result in impaired function. Proteins such as tau, α-synuclein, huntingtin and β-amyloid have all been found to form inclusions in the brain and are linked to the development of a number of neurodegenerative diseases, including Alzheimer's disease and Huntington’s disease. Recently, the TDP-43 protein was identified as one of the major components of protein inclusions that typify the neurogenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia with ubiquitin inclusions (FTLD-U). Abnormalities in TDP- 43 biology appear to be sufficient to cause neurodegenerative disease, as studies have indicated that mutations in TDP-43 occur in familial ALS. In addition, TDP-43 has been found to play a role in the stress granule machinery. Analysis of the biology of the major proteins that accumulate in other neurodegenerative diseases has led to major advances in our understanding of the pathophysiology of TDP-43 inclusions as well as the development of new drug discovery platforms. Tau aggregation is also believed important in pathological processes of disease, in particular neurodegenerative disease.

[0006] Currently, it is believed that aggregates that accumulate in neurodegenerative diseases like ALS, FTLD-U, Parkinson's disease and Huntington's disease accumulate slowly and are very difficult to disaggregate or perhaps cannot be disaggregated. Thus, there is an unmet need for compositions and methods that can rapidly disaggregate these accumulating proteins, more specifically, TDP-43 and tau, or inhibit the formation of aggregates altogether. SUMMARY In an aspect, the disclosure provides a compound of Formula (I): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: E is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E may be optionally substituted; E' is absent, or E' is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E' may be optionally substituted; and R3xand R4are each H or an independently selected optional substituent. In some embodiments, E' is absent. In another aspect, the disclosure provides a compound of Formula (II): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CR14; L1is absent, or L1is C1-C6alkylene, C1-C6heteroalkylene, –O–, –S–, or –NR'–, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted; A is H, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and A may be optionally substituted; or A and R11are taken together with the atoms to which they are attached to form an optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic ring; R11, R12, R13, and R14are each independently H or an optional substituent; each R' is H or C1-C6alkyl; and each of R3xand R4is independently H or an independently selected optional substituent, wherein no more than two of Z1, Z2, Z3and Z4are N. In another aspect, the disclosure provides a compound of Formula (II): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CR14; L1is absent, or L1is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted by 1-4 independently substituents selected from =O (oxo), OH, and halogen; A is H, halo, C1-C10alkyl, C1-C10heteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, 5-6 membered heteroaryl, C6-C10carbocyclyl, or -5- 10 membered heterocyclic ring, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups; or A and R11are taken together with the atoms to which they are attached to form a C3-C7cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, wherein the heteroaryl and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein each of the rings is optionally substituted by one R1group and optionally substituted by 1-4 independently selected R2groups; each of R11, R12, R13, and R14is independently H or R3; R1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C9heteroalkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, or –L2–G, wherein the C1-C6alkyl may be optionally substituted with OH, and wherein the C1-C6heteroalkyl may be optionally substituted with C2-C6heteroalkynyl; L2is absent, or L2is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein alkylene and heteroalkylene are optionally substituted by 1-4 substituents independently selected from =O (oxo), OH, and halogen; G is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, or 5-10 membered heterocyclyl, wherein heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), OH, –NMe2, – NHMe, –NH2, CN, and halo; each R2is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), –OH, –NMe2, –NHMe, –NH2, and halo; each R3is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, cyano, and halo; R4is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, cyano, and halo; each R' is H or C1-C6alkyl; and R3xis selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo, wherein no more than two of Z1, Z2, Z3and Z4are N. In some embodiments, R3xis H or C1-C6alkyl. In some embodiments, R3xis H or –Me. In some embodiments, R4is H, halo, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, or C1-C6heteroalkyl. In some embodiments, R4is H, –Cl, –Br, –OCF3, –Me, –OMe, –Et, –nPr, –iPr, – CH2OCH3, –CH=CH2, or –CH2CH=CH2. In some embodiments, Z1is CR11, Z2is CR12, Z3is CR13, and Z4is CR14. In some embodiments, Z1is N, Z2is CR12, Z3is CR13, and Z4is CR14. In some embodiments, Z1is CR11, Z2is N, Z3is CR13, and Z4is CR14. In some embodiments, Z1is N, Z2is CR12, Z3is N, and Z4is CR14. In some embodiments, Z1is N, Z2is N, Z3is CR13, and Z4is CR14. In some embodiments, Z1is CR11, Z2is N, Z3is CR13, and Z4is N. In some embodiments, each of R11, R12, R13, and R14is independently H or R3, wherein each R3is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, and halo. In some embodiments, each of R11, R12, R13, and R14is independently H or R3, wherein each R3is independently selected from the group consisting of –Me, –Et, –nPr, –iPr, –CF3, –OMe, –OCF3, –OH, –F, and –Cl. In some embodiments, L1is absent. In some embodiments, L1is C1-C6alkylene, C1-C6heteroalkylene, or –O–. In some embodiments, L1is –CH2–, –OCH2–, –NHCH2–, –N(CH3)CH2–, or –O–. In some embodiments, A is selected from the group consisting of halo, C1-C10alkyl, and C1-C10heteroalkyl, wherein the C1-C10alkyl and C1-C10heteroalkyl are optionally substituted by =O (oxo). In some embodiments, A is selected from the group consisting of –F, –Cl, –Me, –Et, – nPr, –iPr, –NHCH3, –N(CH3)2, In some embodiments, A is selected from the group consisting of C3-C7cycloalkyl, 3- 7 membered heterocycloalkyl, C6-C10aryl, 5-6 membered heteroaryl, C6-C10carbocyclyl, and 5-10 membered heterocyclic ring, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups. In some embodiments, A is selected from the group consisting of C3-C7cycloalkyl, 3- 7 membered heterocycloalkyl, C6-C10aryl, and 5-6 membered heteroaryl, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups. In some embodiments, A is selected from the group consisting of , , , , , , , , , , , and . In some embodiments, each R2is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), –OH, –NMe2, – NHMe, –NH2, and halo. In some embodiments, each R2is independently selected from the group consisting of –Me, –Et, –nPr, –iPr, –CF3, –OMe, –OCF3, =O (oxo), –OH, –NMe2, –NHMe, –NH2, F, Cl, and Br. In some embodiments, R1is H or –L2–G. In some embodiments, R1is –L2–G. In some embodiments, L2is absent. In some embodiments, L2is selected from the group consisting of C1-C6alkylene, C1- C6heteroalkylene, and –O–. In some embodiments, L2is –CH2–. In some embodiments, G is C3-C7cycloalkyl or 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl has 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents. In some embodiments, G is 3-7 membered heterocycloalkyl, wherein G may be optionally substituted by 1-4 RAsubstituents. In some embodiments, G is selected from the group consisting of

[0007] In some embodiments, each RAis C1-C6alkyl. In some embodiments, G is selected from the group consisting of In some embodiments, A is selected from the group consisting of

[0008] In some embodiments, A is selected from the group consisting of In some embodiments, A and R11are taken together with the atoms to which they are attached to form a C3-C7cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, wherein the heteroaryl and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, each of the rings optionally substituted by one R1group and optionally substituted by 1-4 independently selected R2groups. In some embodiments, is selected from the group consisting of In some embodiments, is selected from the group consisting of In some embodiments, the compound is of Formula (IIa): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIb): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIc): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IId): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a compound of Formula (III): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: X1is NR1, O, S, SO2, CH2or CHR1; X2is N or CH; R1is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, and –L2–G, wherein the C1-C6alkyl may be optionally substituted with one or more OH, and wherein the C1-C6heteroalkyl may be optionally substituted with C2-C6heteroalkynyl; L2is absent, or L2is selected from the group consisting of C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, and -NR'-, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted by 1-4 substituents independently selected from the group consisting of =O (oxo), OH, and halogen; G is selected from the group consisting of C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, and 5-10 membered heterocyclyl, wherein the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, OH, CN, and halo; each R2is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NH2, and halo; each R3is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, cyano, and halo; R3xis selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; R4is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C9heteroalkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, cyano, and halo; each R' is H or C1-C6alkyl; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. In another aspect, the disclosure provides a compound of Formula (III): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: X1is selected from the group consisting of NR1, O, S, SO2, CH2, and CHR1; X2is N or CH; R1is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, and –G; G is selected from the group consisting of C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, and 5-10 membered heterocyclyl, wherein heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, OH, CN, and halo; each R2is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and halo; each R3is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; R3xis selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; R4is selected from the group consisting of H, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. In some embodiments, the compound is of Formula (IIIa): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, X1is NR1and X2is CH. In some embodiments, X1is CH2or CHR1and X2is N. In some embodiments, X1is NR1and X2is N. In some embodiments, R1is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, OH, and halo. In some embodiments, R1is selected from the group consisting of –Me, –Et, –nPr, – iPr, –OMe, –OCF3, –OH, –Cl, –F, In some embodiments, R3xis H or –Me. In some embodiments, R3xis H. In some embodiments, R4is –Me. In some embodiments, m is 1 and n is 1. In some embodiments, m is 0 and n is 1. In some embodiments, p is 0. In some embodiments, q is 0. In some embodiments, the compound is of Formula (IIIb): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIIc): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIId): or stereoisomer and / or a pharmaceutically acceptable salt thereof In some embodiments, the compound is of Formula (IIIe): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a compound of Formula (IV): or stereoisomer and / or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CH; R11is selected from the group consisting of H, –OH, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy; R12is selected from the group consisting of H, –OH, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy; R13is H or halo; R14is selected from the group consisting of H, halo, C1-C6alkylene, C1-C6heteroalkylene, 5-7 membered aryl, 5-7 membered heteroaryl, and 3-7 membered heterocycloalkyl, wherein the R14may be optionally substituted with one or more R14a; R14ais selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C3-C7cycloalkyl, 5-7 membered aryl, 3-7 membered heterocycloalkyl, and –C(O)OR14b, wherein the C1-C6alkyl or the 3-7 membered heterocycloalkyl may be optionally substituted with one or more R14b; R14bis selected from the group consisting of –OH, oxo, C1-C6alkyl, C1-C8heteroalkyl, C2-C6alkynyl, and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl; wherein when Z2is CR12, R12and R14may be taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, or aryl, wherein the cycloalkyl or heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl; R3xis H or C1-C6alkyl; and R4is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C1-C6haloalkoxy. In some embodiments, Z1is CR11, Z2is CR12, Z3is CR13, and Z4is CH. In some embodiments, when Z1is N, Z2is CR12, Z3is CR13, and Z4is CH. In some embodiments, when Z2is N, Z1is CR11, Z3is CR13, and Z4is CH. In some embodiments, when Z2and Z3are N, Z1is CR11and Z4is CH. In some embodiments, when Z2and Z4are N, Z1is CR11and Z3is CR13. In some embodiments, R11and R12are selected from the group consisting of halo, C1- C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy. In some embodiments, R11and R12are selected from the group consisting of –Me, – Et, –Cl, –F, –OMe, and –OCF3. In some embodiments, R11or R12is –OH. In some embodiments, R13is halo. In some embodiments, R13is –Cl. In some embodiments, R14is selected from the group consisting of H, halo, C1-C3alkylene, C1-C6heteroalkylene, phenyl, 5 membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C1-C3alkylene, C1-C6heteroalkylene, phenyl, 5 membered heteroaryl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of ethyl, –O–, –CH2– , –nPr, –iPr, -Cl, NHCH3, –N(CH3)2, wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of –Et, –nPr, –iPr, - Cl, NHCH3, –N(CH3)2, wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of , In some embodiments, R14ais selected from the group consisting of C1-C3alkyl, C1- C6heteroalkyl, C3-C6cycloalkyl, 6 membered aryl, and 4-6 membered heterocycloalkyl, wherein C1-C6heteroalkyl, C3-C7cycloalkyl, and 5-7 membered aryl may be optionally substituted with R14b. In some embodiments, R14ais selected from the group consisting of –Me, –Et, –CH2–, nPr, , , , , , , , wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of –Me, –Et, nPr, and wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of –C(O)OR14b, In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, C3-C7heteroalkyl, C2-C3alkynyl, and 6 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl. In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, may be optionally substituted with oxo or C1-C6alkyl. In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, may be optionally substituted with –Me. In some embodiments, when Z2is CR12, R12and R14may be taken together with the atoms to which they are attached to form an aryl, cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl. In some embodiments, when Z2is CR12, R12and R14taken together are selected from the group consisting of In some embodiments, R3xis C1-C6alkyl. In some embodiments, R3xis –Me. In some embodiments, R4is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C1-C6haloalkoxy. In some embodiments, R4is selected from the group consisting of –Cl, –Br, –OCF3, – Me, –Et, –OMe, In another aspect is a compound selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of the previous embodiments. In another aspect is a method of treating a subject with a neurodegenerative disease or disorder, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition or a compound of any one of the previous embodiments. In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler's disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder's disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler- Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), and autism, or any combination thereof. In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 depicts Compound 183 preventing TDP-43 nuclear clearance following proteasome inhibition. Representative micrographs of iP11NA human motor neurons unstressed, those treated with MG-132 (1 μM), or a combination of Compound 183 (500 nM) and MG-132 (1 μM) immunostained for TDP-43 (green), ȕ-III tubulin (red) and counterstained with Hoechst (blue). Magnified images from the 3 conditions highlight the change from nuclear TDP-43 in unstressed neurons, to diffuse staining in cells under proteasomal stress, to maintenance of nuclear TDP-43 in the presence of Compound 183. FIG.2 depicts Compound 183 maintaining nuclear TDP-43 in a dose-dependent manner. (a) Representative micrographs of iP11NA human motor neurons treated with MG-132 (1 μM) and Compound 183 (indicated concentrations) immunostained for TDP-43 (green), ȕ-III tubulin (pink), human nuclear antigen (red) and counterstained with Hoechst (blue). (b) Differential TDP-43 immunostaining intensity (nuclear (ROI) – cytoplasmic (ROI)) for human motor neurons unstressed (gray) or treated with MG-132 (red, 1 μM) and Compound 183 (indicated concentration). Data are displayed as dots representing replicate wells with mean and S.D. Statistical analysis performed with one-way ANOVA and Dunnett’s multiple caparisons test. FIG.3 depicts Compound 183 reducing aggregated TDP-43, a pathological hallmark of ALS, and restoring nuclear TDP-43 localization. Immunoblot analysis of TDP-43 in the indicated fractions from neurons unstressed, treated with MG-132 (1 μM), or a combination of Compound 183 (500 nM) and MG-132 (1 μM) Data are displayed as bars with S.D. Statistical analysis performed with one-way ANOVA and Dunnett’s multiple caparisons test. FIG.4 depicts proteasome inhibition induces splicing changes associated with TDP-43 loss- of-function. qRT-PCR analysis of TDP-43 sentinel transcripts (STMN2, ELAVL3, and PFKP) expression in human motor neurons treated with puromycin (10 mg / mL) or MG-132 (1 μM) relative unstressed samples. Data are displayed as dots representing replicate wells with mean and S.D. FIG.5 depicts Compound 183 restoring splicing function of TDP-43 that is lost in ALS. qRT-PCR analysis of TDP-43 sentinel transcripts (STMN2, ELAVL3, and PFKP) expression for human motor neurons treated with MG-132 (1 μM) and Compound 183 (500 nM) relative to MG-132 (1 μM) control. FIG.6 depicts Compound 183 restoring TDP-43 splicing function in dose dependent manner. qRT-PCR analysis of TDP-43 sentinel transcripts (STMN2, ELAVL3, and PFKP) expression for human motor neurons unstressed (gray) or treated with MG-132 (1 μM) and Compound 183 (indicated concentration) relative to MG-132 (1 μM) control. Data are displayed as dots representing replicate wells with mean and S.D. Statistical analysis performed with one-way ANOVA and Dunnett’s multiple caparisons test. DETAILED DESCRIPTION

[0009] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that occurs with an incidence of approximately 1 / 100,000. There is currently no therapy for ALS, and the average survival time of patients from the onset of the disease is roughly four years. ALS presents with motor weakness in the distal limbs that rapidly progresses proximally. Studies over the past decade have indicated that TDP-43 is the major protein that accumulates in affected motor neurons in sporadic ALS. The causes of sporadic ALS are not known, but identification of the major pathological species accumulating in the spinal cord of ALS patients represents a seminal advance for ALS research. To date, TDP-43 is the only protein that has been both genetically and pathologically linked with sporadic ALS, which represents the predominant form of the disease. Multiple papers have identified mutations in TDP-43 associated with sporadic and familial ALS. Inhibitors of cell death and inclusions linked to TDP-43 represent a novel therapeutic approach to ALS, and may also elucidate the biochemical pathway linked to the formation of TDP-43 inclusions. As such, TDP-43 represents one of the most promising targets for pharmacotherapy of ALS.

[0010] TDP-43 is a nuclear RNA binding protein that translocates to the cytoplasm in times of cellular stress, where it forms cytoplasmic inclusions. These inclusions then colocalize with reversible protein-mRNA aggregates termed “stress granules” (SGs). Under many stress-inducing conditions (e.g., arsenite treatment, nutrient deprivation), TDP-43 can colocalize with SGs. The reversible nature of SG-based aggregation offers a biological pathway that might be applied to reverse the pathology and toxicity associated with TDP-43 inclusion formation. Studies show that agents that inhibit SG formation also inhibit formation of TDP- 43 inclusions. The relationship between TDP-43 and stress granules is important because it provides a novel approach for dispersing TDP-43 inclusions using physiological pathways that normally regulate this reversible SG process. Investigating the particular elements of the SG pathway that regulate TDP-43 inclusion formation can identify selective approaches for therapeutic intervention to delay or halt the progression of disease. Stress granule biology also regulates autophagy and apoptosis, both of which are linked to neurodegeneration. Hence, compounds inhibiting TDP-43 aggregation may play a role in inhibiting neurodegeneration.

[0011] Tau is a protein known to be present in a number of pathological conditions, particularly neurodegenerative disorders including Alzheimer's disease. Hence, compounds inhibiting tau aggregation may play a role in inhibiting neurodegeneration. Compounds Accordingly, in an aspect, the disclosure provides a compound of Formula (I): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: E is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E may be optionally substituted; E' is absent, or E' is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E' may be optionally substituted; and R3xand R4are each H or an independently selected optional substituent. In some embodiments, E' is absent. In some embodiments, E' is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E' may be optionally substituted. In some embodiments, the compound is of Formula (Ia): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (II): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CR14; L1is absent, or L1is C1-C6alkylene, C1-C6heteroalkylene, –O–, –S–, or –NR'–, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted; A is H, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and A may be optionally substituted; or A and R11are taken together with the atoms to which they are attached to form an optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic ring; R11, R12, R13, and R14are each independently H or an optional substituent; each R' is H or C1-C6alkyl; and each of R3xand R4is independently H or an independently selected optional substituent, wherein no more than two of Z1, Z2, Z3and Z4are N. In some embodiments, the compound is of Formula (II): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CR14; L1is absent, or L1is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted by 1-4 independently substituents selected from =O (oxo), OH, and halogen; A is H, halo, C1-C10alkyl, C1-C10heteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, 5-6 membered heteroaryl, C6-C10carbocyclyl, or 5- 10 membered heterocyclic ring, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups; or A and R11are taken together with the atoms to which they are attached to form a C3-C7cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, wherein the heteroaryl and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein each of the rings is optionally substituted by one R1group and optionally substituted by 1-4 independently selected R2groups; each of R11, R12, R13, and R14is independently H or R3; R1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, or –L2–G; L2is absent, or L2is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein alkylene and heteroalkylene are optionally substituted by 1-4 substituents independently selected from =O (oxo), OH, and halogen; G is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, or 5-10 membered heterocyclyl, wherein the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), OH, –NMe2, –NHMe, –NH2, CN, and halo; each R2is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), –OH, –NMe2, – NHMe, –NH2, or halo; each R3is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6haloalkyl, C1-C6haloalkoxy, OH, cyano, or halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, cyano, or halo; each R' is H or C1-C6alkyl; and R3xis H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, or halo, wherein no more than two of Z1, Z2, Z3and Z4are N. In some embodiments, R3xis H or C1-C6alkyl. In some embodiments, R3xis H or – Me. In some embodiments, R3xis H. In some embodiments, R3xis –Me. In some embodiments, R4is H, C1-C6alkyl, C2-C6alkenyl, or C1-C6heteroalkyl. In some embodiments, R4is H, –Me, –Et, –nPr, –iPr, –CH2OCH3, –CH=CH2, or –CH2CH=CH2. In some embodiments, Z1is CR11, Z2is CR12, Z3is CR13, and Z4is CR14. In some embodiments, Z1is N, Z2is CR12, Z3is CR13, and Z4is CR14. In some embodiments, Z1is CR11, Z2is N, Z3is CR13, and Z4is CR14. In some embodiments, Z1is N, Z2is CR12, Z3is N, and Z4is CR14. In some embodiments, Z1is N, Z2is N, Z3is CR13, and Z4is CR14. In some embodiments, Z1is CR11, Z2is N, Z3is CR13, and Z4is N. In some embodiments, each of R11, R12, R13, and R14is independently H or R3, wherein each R3is independently C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, or halo. In some embodiments, each of R11, R12, R13, and R14is independently H or R3, wherein each R3is independently –Me, –Et, , –nPr, –iPr, –CF3, –OMe, –OCF3, –OH, –F, or – Cl. In some embodiments, R11is H. In some embodiments, R12is H. In some embodiments, R13is H. In some embodiments, R14is H. In some embodiments, each of R11, R12, R13, and R14is H. In some embodiments, L1is absent. In some embodiments, L1is C1-C6alkylene, C1-C6heteroalkylene, or –O–. In some embodiments, L1is –CH2–, –OCH2–, –NHCH2–, –N(CH3)CH2–, or –O–. In some embodiments, L1is –CH2–. In some embodiments, L1is –OCH2–. In some embodiments, L1is –NHCH2–. In some embodiments, L1is –N(CH3)CH2–. In some embodiments, L1is –O–. In some embodiments, A is halo, C1-C10alkyl, or C1-C10heteroalkyl, wherein the C1- C10alkyl and C1-C10heteroalkyl are optionally substituted by =O (oxo). In some embodiments, A is –F, –Cl, –Me, –Et, –nPr, –iPr, –NHCH3, –N(CH3)2, In some embodiments, A is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, 5-6 membered heteroaryl, C6-C10carbocyclyl, or 5-10 membered heterocyclic ring, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups. In some embodiments, A is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, or 5-6 membered heteroaryl, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups. In some embodiments, each R2is independently C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), –OH, –NMe2, –NHMe, –NH2, or halo. In some embodiments, each R2is independently –Me, –Et, –nPr, –iPr, –CF3, –OMe, – OCF3, =O (oxo), –OH, –NMe2, –NHMe, –NH2, F, Cl, or Br. In some embodiments, R1is H or –L2–G. In some embodiments, R1is H. In some embodiments, R1is –L2–G. In some embodiments, L2is absent. In some embodiments, L2is C1-C6alkylene, C1- C6heteroalkylene, or –O–. In some embodiments, L2is –CH2–. In some embodiments, G is C3-C7cycloalkyl or 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl has 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents. In some embodiments, G is 3-7 membered heterocycloalkyl, wherein G may be optionally substituted by 1-4 RAsubstituents. In some embodiments, G is In some embodiments, each RAis independently selected from C1-C6alkyl.

[0012] In some embodiments, A and R11are taken together with the atoms to which they are attached to form a C3-C7cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, wherein the heteroaryl and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, each of the rings optionally substituted by one R1group and optionally substituted by 1-4 independently selected R2groups.

[0013]

[0014] In some embodiments, the compound is of Formula (Ila): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIb): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIc): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IId): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (III): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: X1is NR1, O, S, SO2, CH2or CHR1; X2is N or CH; R1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, or –L2–G; L2is absent, or L2is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein alkylene and heteroalkylene are optionally substituted by 1-4 substituents independently selected from =O (oxo), OH, and halogen; G is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, or 5-10 membered heterocyclyl, wherein heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, OH, CN, or halo; each R2is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NH2, or halo; each R3is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6haloalkyl, C1-C6haloalkoxy, OH, cyano, or halo; R3xis H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, or halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, , C1-C6haloalkyl, cyano, or halo; each R' is H or C1-C6alkyl; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. In some embodiments, the compound is of Formula (III): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: X1is NR1, O, S, SO2, CH2or CHR1; X2is N or CH; R1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, or –G; G is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, or 5-10 membered heterocyclyl, wherein heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, OH, CN, or halo; each R2is independently C1-C6alkyl, C1-C6haloalkyl, or halo; each R3is independently C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, or halo; R3xis H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, or halo; R4is H, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, or halo; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. In some embodiments, X1is NR1. In some embodiments, X1is CH2or CHR1. In some embodiments, X2is CH. In some embodiments, X2is N. In some embodiments, X1is NR1and X2is CH. In some embodiments, X1is CH2or CHR1and X2is N. In some embodiments, X1is NR1and X2is N. In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is –Me, –Et, –nPr, –iPr, In some embodiments, R3xis H or C1-C6alkyl. In some embodiments, R3xis H or – Me. In some embodiments, R3xis H. In some embodiments, R3xis –Me. In some embodiments, R4is C1-C6alkyl. In some embodiments, R4is –Me, –Et, –nPr, –iPr, In some embod4 iments, R is –Me. In some embodiments, R4is halo, C1-C6haloalkoxy, or C1-C6alkoxy. In some embodiments, R4is – Cl, –Br, –OCF3, –OMe, In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 1 and n is 1. In some embodiments, m is 0 and n is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, the compound is of Formula (IIIa): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIIb): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIIc): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIId): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIIe): or stereoisomer and / or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Formula (IV): or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CH; R11is selected from the group consisting of H, –OH, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy; R12is selected from the group consisting of H, –OH, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy; R13is H or halo; R14is selected from the group consisting of H, halo, C1-C6alkylene, C1-C6heteroalkylene, 5-7 membered aryl, 5-7 membered heteroaryl, and 3-7 membered heterocycloalkyl, wherein the R14may be optionally substituted with one or more R14a; R14ais selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C3-C7cycloalkyl, 5-7 membered aryl, 3-7 membered heterocycloalkyl, and –C(O)OR14b, wherein the C1-C6alkyl or the 3-7 membered heterocycloalkyl may be optionally substituted with one or more R14b; R14bis selected from the group consisting of –OH, oxo, C1-C6alkyl, C1-C8heteroalkyl, C2-C6alkynyl, and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl; wherein when Z2is CR12, R12and R14may be taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, or aryl, wherein the cycloalkyl or heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl; R3xis H or C1-C6alkyl; and R4is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C1-C6haloalkoxy. In some embodiments, Z1is CR11, Z2is CR12, Z3is CR13, and Z4is CH. In some embodiments, when Z1is N, Z2is CR12, Z3is CR13, and Z4is CH. In some embodiments, when Z2is N, Z1is CR11, Z3is CR13, and Z4is CH. In some embodiments, when Z2and Z3are N, Z1is CR11and Z4is CH. In some embodiments, when Z2and Z4are N, Z1is CR11and Z3is CR13. In some embodiments, R11is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy. In some embodiments, R12is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy. In some embodiments, R11is selected from the group consisting of –Me, –Et, –Cl, –F, –OMe, and –OCF3. In some embodiments, R12is selected from the group consisting of –Me, –Et, –Cl, –F, –OMe, and –OCF3. In some embodiments, R11is –OH. In some embodiments, R12is –OH. In some embodiments, R13is halo. In some embodiments, R13is –Cl. In some embodiments, R14is selected from the group consisting of H, halo, C1-C3alkylene, C1-C6heteroalkylene, 6 membered aryl, 5 membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C1-C3alkylene, C1-C6heteroalkylene, 6 membered aryl, 5 membered heteroaryl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of –Et, –O–, –CH2–, –nPr, –iPr, -Cl, NHCH3, –N(CH3)2, wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of –Et, –O–, –CH2–, –nPr, –iPr, and –Cl, wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of NHCH3, –N(CH3)2, wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of , wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of –Et, –nPr, –iPr, - Cl, NHCH3, –N(CH3)2, whe14 rein if R contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of –Et, –nPr, –iPr, and –Cl, wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of NHCH3, –N(CH3)2, whe14 rein if R contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of , wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a. In some embodiments, R14is selected from the group consisting of , , , , , , In some embodiments, R14is selected from the group consisting of In14 some embodiments, R is selected from the group consisting of , , , , , , In some embodiments, R14ais selected from the group consisting of C1-C3alkyl, C1- C6heteroalkyl, C3-C6cycloalkyl, 6 membered aryl, and 4-6 membered heterocycloalkyl, wherein C1-C6heteroalkyl, C3-C7cycloalkyl, and 5-7 membered aryl may be optionally substituted with R14b. In some embodiments, R14ais selected from the group consisting of –Me, –Et, –CH2–, nPr, , wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of –Me, –Et, –CH2–, and nPr, wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of –Me, –Et, nPr, and , wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of –Me, –Et, and nPr, wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting , wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of , wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b. In some embodiments, R14ais selected from the group consisting of –C(O)OR14b, In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, C3-C7heteroalkyl, C2-C3alkynyl, and 6 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl. In some embodiments, R14bis selected from the group consisting of oxo, –OH, and –Me. In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, may be optionally substituted with oxo or C1-C6alkyl. In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, and . In some embodiments, R14bmay be optionally substituted with oxo or C1-C6alkyl. In some embodiments, R14bis selected from the group consisting of oxo, –OH, –Me, wherein the and may be optionally substituted with –Me. In some embodiments, R14bmay be optionally substituted with –Me. In some embodiments, when Z2is CR12, R12and R14may be taken together with the atoms to which they are attached to form an aryl, cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl. In some embodiments, when Z2is CR12, R12and R14taken together are selected from the group consisting of In some embodiment12 14 s, R and R taken together is In some embodiments, when Z2is CR12, R12and R14taken together are selected from the group consisting of In some embodiments, when Z2is CR12, R12and14 R taken together are selected from the group consisting of In some embodiments, R3xis C1-C6alkyl. In some embodiments, R3xis C1-C3alkyl. In some embodiments, R3xis –Me. In some embodiments, R3xis –Et. In some embodiments, R3xis nPr. In some embodiments, R3xis iPr. In some embodiments, R4is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C1-C6haloalkoxy. In some embodiments, R4is selected from the group consisting of –Cl, –Br, –OCF3, – Me, –Et, –OMe, In some embodiments, R4is selected from the group consisting of –Cl, –Br, –OCF3, –Me, –Et, –OMe. In some embodiments, R4 is selected from the group consisting of In some embodiments, the compound is selected from a compound disclosed in the specification or figures. In some embodiments, provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the compound of Formula (I), (II), (III), or (IV) is selected from a compound disclosed in the specification or figures. In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any one of the compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the compound of Formula (I), (II), (III), or (IV), or subformulas thereof, is selected from the compounds in Table 1. Table 1: Exemplary compounds of the disclosure

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022] Methods of Treatment and Use

[0023] In the following methods, use of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) can also refer to use of a pharmaceutical composition including a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In an aspect, the disclosure provides methods for treating a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), or a viral infection in a subject in need thereof, the methods generally comprise administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the subject is suffering from a neurodegenerative disease or disorder. In some embodiments, the subject is suffering from a musculoskeletal disease or disorder. In some embodiments, the subject is suffering from a cancer. In some embodiments, the subject is suffering from an ophthalmological disease or disorder (e.g., a retinal disease or disorder). In some embodiments, the subject is suffering from a viral infection. In some embodiments, the disclosure provides methods for treating a neurodegenerative disease or disorder, the methods comprise administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods for treating a musculoskeletal disease or disorder, the methods comprise administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods for treating a cancer, the methods comprise administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods for treating an ophthalmological disease or disorder (e.g., a retinal disease or disorder), the methods comprise administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods for treating a viral infection, the methods comprise administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), or a viral infection prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with a musculoskeletal disease or disorder prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with a cancer prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with an ophthalmological disease or disorder (e.g., a retinal disease or disorder) prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the methods further comprise the step of diagnosing the subject with a viral infection prior to administration of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In another aspect, the disclosure provides methods of diagnosing a neurodegenerative disease, a musculoskeletal disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection in a subject, the methods generally comprise administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject. In some embodiments, the disclosure provides methods of diagnosing a neurodegenerative disease in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject. In some embodiments, the disclosure provides methods of diagnosing a musculoskeletal disease in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods of diagnosing a cancer in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods of diagnosing an ophthalmological disease (e.g., a retinal disease) in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the disclosure provides methods of diagnosing a viral infection in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the subject is a mammal. In some embodiments, the subject is a nematode. In some embodiments, the subject is human. Stress Granules and TDP-43 By comprising stress granules is meant that number of stress granules in a cell in the subject is changed relative to a control or healthy subject or relative to before onset of said disease or disorder. Exemplary diseases and disorders pathology of which incorporate stress granules include, but are not limited to, neurodegenerative diseases, musculoskeletal diseases, cancers, ophthalmological diseases (e.g., retinal diseases), and viral infections. TDP-43 and other RNA-binding proteins function in both the nucleus and cytoplasm to process mRNA, e.g., by splicing mRNA, cleaving mRNA introns, cleaving untranslated regions of mRNA or modifying protein translation at the synapse, axon, dendrite or soma. Therefore, targeting other proteins that function in an analogous manner to TDP-43 or by processing mRNA may also be beneficial to prevent and treat neurodegeneration resulting from disease. For instance, the fragile X mental retardation 1 (FMRP) protein is essential for normal cognitive development. The signaling systems that affect TDP-43 function might also affect this protein, thus improving cognitive function. This can be particularly important at the synapse where neurons communicate. Without being bound by a theory, the signaling systems that compounds of Formula (I), (II), or (III) target may also modify these processes, which play a role in neurodegeneration or mental health illnesses (e.g., schizophrenia). The cellular stress response follows a U-shaped curve. Overinduction of this pathway, such as observed in many neurodegenerative diseases, can be harmful for cells. However, a decreased stimulation of this pathway can also be harmful for cells, e.g., in the case of an acute stress, such as a stroke. Thus, the appropriate action for some diseases is the inhibition of stress granule formation, while for other diseases, stimulation of stress granule formation is beneficial. In some embodiments, the TDP-43 protein in a stress granule may be wild-type or a mutant form of TDP-43. In some embodiments, the mutant form of TDP-43 comprises an amino acid addition, deletion, or substitution, e.g., relative to the wild type sequence of TDP- 43. In some embodiments, the mutant form of TDP-43 comprises an amino acid substitution relative to the wild type sequence (e.g., a G294A, A135T, Q331K, or Q343R substitution). In some embodiments, the TDP-43 protein in a stress granule comprises a post-translational modification (e.g., phosphorylation of an amino acid side chain (e.g., T103, S104, S409, or S410)). In some embodiments, the pathology of the neurodegenerative disease or disorder, the musculoskeletal disease or disorder, the cancer, the ophthalmological disease or disorder, or the viral infection comprises stress granules. In some embodiments, the pathology of the neurodegenerative disease, the musculoskeletal disease or disorder, the cancer, the ophthalmological disease or disorder, or the viral infection comprises TDP-43 inclusions. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject inhibits the formation of a stress granule. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject inhibits the formation of a stress granule by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete inhibition) relative to a control (e.g., a baseline of the formation of a stress granule in the subject; the formation of a stress granule in the subject prior to administering a compound disclosed herein; the formation of a stress granule in a subject not receiving a compound disclosed herein; or the formation of a stress granule in a subject receiving a placebo). In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to a subject in need thereof disaggregates a stress granule. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), or (III) or subformulas thereof, or a compound of Table 1) to the subject disperses or disaggregate a stress granule by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete dispersal) relative to a control (e.g., a baseline of the disaggregation of a stress granule in the subject; the disaggregation of a stress granule in the subject prior to administering a compound disclosed herein; the disaggregation of a stress granule in a subject not receiving a compound disclosed herein; or the disaggregation of a stress granule in a subject receiving a placebo). In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to a subject in need thereof reduces a stress granule level. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), or (III) or subformulas thereof, or a compound of Table 1) to the subject reduces a stress granule level by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% relative to a control (e.g., a baseline of the stress granule level in the subject; the stress granule level in the subject prior to administering a compound disclosed herein; the stress granule level in a subject not receiving a compound disclosed herein; or the stress granule level in a subject receiving a placebo). In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP-43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP- 1), GTPase activating protein binding protein 2 (G3BP-2), tris tetraprolin (TTP, ZFP36), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP, FMR1). In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP-43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP- 1), GTPase activating protein binding protein 2 (G3BP-2), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP, FMR1). In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP-43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP- 1), GTPase activating protein binding protein 2 (G3BP-2), or fused in sarcoma (FUS). In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP-43). In some embodiments, the stress granule comprises T-cell intracellular antigen 1 (TIA-1). In some embodiments, the stress granule comprises TIA-1 cytotoxic granule- associated RNA binding protein-like 1 (TIAR, TIAL1). In some embodiments, the stress granule comprises GTPase activating protein binding protein 1 (G3BP-1). In some embodiments, the stress granule comprises GTPase activating protein binding protein 2 (G3BP-2). In some embodiments, the stress granule comprises tris tetraprolin (TTP, ZFP36). In some embodiments, the stress granule comprises fused in sarcoma (FUS). In some embodiments, the stress granule comprises fragile X mental retardation protein (FMRP, FMR1). In another aspect, the disclosure provides methods of modulating TDP-43 inclusion formation in a subject, the methods generally comprise administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to a subject in need thereof. In some embodiments, TDP-43 inclusion formation is inhibited. In some embodiments, the TDP-43 inclusion is disaggregated. In some embodiments, TDP-43 inclusion formation is stimulated. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject inhibits the formation of a TDP-43 inclusion. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject inhibits the formation of a TDP-43 inclusion by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete inhibition) relative to a control (e.g., a baseline of the formation of a TDP-43 inclusion in the subject; the formation of a TDP-43 inclusion in the subject prior to administering a compound disclosed herein; the formation of a TDP-43 inclusion in a subject not receiving a compound disclosed herein; or the formation of a TDP-43 inclusion in a subject receiving a placebo). In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject disaggregates a TDP-43 inclusion. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject disperses or disaggregates a TDP-43 inclusion by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete dispersal) relative to a control (e.g., a baseline of the disaggregation of a TDP-43 in the subject; the disaggregation of a TDP-43 in the subject prior to administering a compound disclosed herein; the disaggregation of a TDP- 43 in a subject not receiving a compound disclosed herein; or the disaggregation of a TDP-43 in a subject receiving a placebo). In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) modulates the post-translational modification of the TDP-43 protein in a stress granule. In another aspect, the disclosure provides methods of modulating tau aggregate formation in a subject, the methods generally comprise administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to a subject in need thereof. In some embodiments, tau aggregate formation is inhibited. In some embodiments, the tau aggregate is disaggregated. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject inhibits the formation of a tau aggregate. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject inhibits the formation of a tau aggregate by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete inhibition) relative to a control (e.g., a baseline of the formation of a tau aggregate in the subject; the formation of a tau aggregate in the subject prior to administering a compound disclosed herein; the formation of a tau aggregate in a subject not receiving a compound disclosed herein; or the formation of a tau aggregate in a subject receiving a placebo). In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject disaggregates a tau aggregate. In some embodiments, administering a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject disperses or disaggregates a tau aggregate by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete dispersal) relative to a control (e.g., a baseline of the disaggregation of a tau aggregate in the subject; the disaggregation of a tau aggregate in the subject prior to administering a compound disclosed herein; the disaggregation of a tau aggregate in a subject not receiving a compound disclosed herein; or the disaggregation of a tau aggregate in a subject receiving a placebo). Neurodegenerative Diseases Without being bound by a theory, compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) can be used to delay the progression of neurodegenerative illnesses where the pathology incorporates stress granules. Such illnesses include ALS and frontotemporal dementia, in which TDP-43 or tau is the predominant protein that accumulates to form the pathology. This group also includes Alzheimer’s disease and FTLD-U, where TDP-43 and other stress granule proteins co-localize with tau pathology. Because modulators of TDP-43 inclusions, such as compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof), can act to block the enzymes that signal stress granule formation (e.g., the three enzymes that phosphorylate eIF2a: PERK, GCN2 and HRI), compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) may also reverse stress granules that might not include TDP-43. Accordingly, compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) can be used for treatment of neurodegenerative diseases and disorders in which the pathology incorporates stress granules, such as Huntington’s chorea and Creutzfeld-Jacob disease. Compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) may also be used for treatment of neurodegenerative diseases and disorders that involve TDP-43 multisystem proteinopathy. The term “neurodegenerative disease” as used herein, refers to a neurological disease characterized by loss or degeneration of neurons. The term “neurodegenerative disease” includes diseases caused by the involvement of genetic factors or the cell death (apoptosis) of neurons attributed to abnormal protein accumulation and so on. Additionally, neurodegenerative diseases include neurodegenerative movement disorders and neurodegenerative conditions relating to memory loss or dementia. Neurodegenerative diseases include tauopathies and α-synucleopathies. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer’s disease, frontotemporal dementia (FTD), FTLD- U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin- deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick’s disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, Down’s syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, Lytigo- bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler- Scheinker syndrome, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) and autism. As used herein, the term “α-synucleopathy” refers to a neurodegenerative disorder or disease involving aggregation of α-synuclein or abnormal α-synuclein in nerve cells in the brain. ^-Synucleopathies include, but are not limited to, Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, Pick’s disease, Down’s syndrome, multiple system atrophy, amyotrophic lateral sclerosis (ALS), Hallervorden-Spatz syndrome, and the like. As used herein, the term “tauopathy” refers to a neurodegenerative disease associated with the pathological aggregation of tau protein in the brain. Tauopathies include, but are not limited to, Alzheimer’s disease, Pick’s disease, corticobasal degeneration, Argyrophilic grain disease (AGD), progressive supranuclear palsy, Frontotemporal dementia, Frontotemporal lobar degeneration, or Pick’s complex. In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeldt-Jacob disease, bovine spongiform encephalopathy, Kuru, and scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick’s disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, Down’s syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease), SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) autism, other diseases or disorders relating to the aberrant expression of or aggregation of TDP-43 or tau and altered proteostasis, and any combination thereof. In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, Creutzfeld-Jacob disease, senile dementia, Parkinsonism linked to chromosome 17 (FTDP- 17), progressive supranuclear palsy (PSP), Pick’s disease, primary progressive aphasia, corticobasal dementia, Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, Down’s syndrome, multiple system atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, spinal degenerative disease / motor neuron degenerative diseases, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis- parkinsonism dementia), hippocampal sclerosis, corticobasal degeneration, Alexander disease, Cockayne syndrome, and any combination thereof. In some embodiments, the neurodegenerative disease is frontotemporal dementia (FTD). In some embodiments, the neurodegenerative disease is Alzheimer’s disease or amyotrophic lateral sclerosis (ALS). Musculoskeletal Diseases Musculoskeletal diseases and disorders as defined herein are conditions that affect the muscles, ligaments, tendons, and joints, as well as the skeletal structures that support them. Without being bound by a theory, aberrant expression of certain proteins, such as the full- length isoform of DUX4, has been shown to inhibit protein turnover and increase the expression and aggregation of cytotoxic proteins including insoluble TDP-43 in skeletal muscle cells (Homma, S. et al. Ann Clin Transl Neurol (2015) 2:151-166). As such, compounds of Formula (I), (II), or (III) may be used to prevent or treat a musculoskeletal disease, e.g., a musculoskeletal disease that results in accumulation of TDP-43 and other stress granule proteins, e.g., in the nucleus, cytoplasm, or cell bodies of a muscle cell or motor neuron. Exemplary musculoskeletal diseases include muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Friedrich’s ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sarcopenia, spasticity, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis. In addition, compounds of Formula (I), (II), or (III) may be used to prevent or treat symptoms caused by or relating to said musculoskeletal diseases, e.g., kyphosis, hypotonia, foot drop, motor dysfunctions, muscle weakness, muscle atrophy, neuron loss, muscle cramps, altered or aberrant gait, dystonias, astrocytosis (e.g., astrocytosis in the spinal cords), liver disease, inflammation, headache, pain (e.g., back pain, neck pain, leg pain, inflammatory pain), and the like. In some embodiments, a musculoskeletal disease or a symptom of a musculoskeletal disease may overlap with a neurodegenerative disease or a symptom of a neurodegenerative disease. In some embodiments, the musculoskeletal disease is selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Friedrich’s ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sarcopenia, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression or aggregation of TDP-43 or tau and altered proteostasis. In some embodiments, a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) may be used to prevent or treat symptoms caused by or relating to said musculoskeletal diseases, e.g., kyphosis, hypotonia, foot drop, motor dysfunctions, muscle weakness, muscle atrophy, neuron loss, muscle cramps, altered or aberrant gait, dystonias, astrocytosis (e.g., astrocytosis in the spinal cords), liver disease, respiratory disease or respiratory failure, inflammation, headache, and pain (e.g., back pain, neck pain, leg pain, or inflammatory pain). Cancers Cancer cells grow quickly and in low oxygen environments by activating different elements of the cellular stress response. Researchers have shown that drugs targeting different elements of the stress response can be anti-neoplastic. For example, rapamycin blocks mTOR, upregulates autophagy and inhibits some types of tumors. Proteasomal inhibitors, such as velcade (Millennium Pharma) are used to treat some cancers. HSP90 inhibitors, such as 17-allylaminogeldanamycin (17AAG), are currently in clinical trials for cancer. Without being bound by a theory, compounds of Formula (I), (II), or (III) may also be used for treatment of cancer, as a greater understanding of the role of TDP-43 in RNA processing and transcription factor signaling has recently begun to emerge. Additionally, TDP-43 modulators can be combined with one or more cancer therapies, such as chemotherapy and radiation therapy. A “cancer” in a subject refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Often, cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells. Examples of cancer include but are not limited to breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a chondrosarcoma, cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and the like. Other exemplary cancers include, but are not limited to, ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing’s sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, ophthalmological cancer, Hodgkin’s lymphoma, Kaposi’s sarcoma, kidney cancer, liver cancer, lung cancer (small or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin’s lymphoma, osteosarcoma, ovarian cancer, ovary (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, Wilm’s tumor, and the like. Exemplary lymphomas include Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Further exemplification of non-Hodgkin’s lymphoma include, but are not limited to, B-cell lymphomas (e.g., diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and T-cell lymphomas (e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g., smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy-associated intestinal T-cell lymphoma (EATL) (e.g., Type I EATL and Type II EATL), and anaplastic large cell lymphoma (ALCL)).

[0024] In some embodiments, the cancer is selected from the group consisting of breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a chondrosarcoma, cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and any combination thereof.

[0025] In some embodiments, the cancer is selected from the group consisting of blastoma, carcinoma, a glioblastoma, hepatic carcinoma, lymphoma, leukemia, and any combination thereof.

[0026] In some embodiments, the cancer is selected from Hodgkin’s lymphoma or nonHodgkin’s lymphoma. In some embodiments, the cancer is a non-Hodgkin’s lymphoma, selected from the group consisting of a B-cell lymphoma (e.g., diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and a T-cell lymphoma (e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g., smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy- associated intestinal T-cell lymphoma (EATL) (e.g., Type I EATL and Type II EATL), and anaplastic large cell lymphoma (ALCL)). Ophthalmological Diseases Ophthalmological diseases and disorders (e.g., retinal diseases and disorders) as defined herein affect the retina and other parts of the eye and may contribute to impaired vision and blindness. Several ophthalmological diseases (e.g., retinal diseases) are characterized by the accumulation of protein inclusions and stress granules within or between cells of the eye, e.g., retinal cells and nearby tissues. In addition, an ophthalmological disease (e.g., retinal disease) may also be a symptom of or precursor to neurogenerative diseases, such as ALS and FTD. Therefore, use of compounds that may inhibit formation of protein inclusions and stress granules, including compounds of Formula (I), (II), (III), or (IV), may play an important role in the prevention or treatment of ophthalmological diseases (e.g., retinal diseases). Exemplary ophthalmological diseases (e.g., retinal diseases) include, but are not limited to, macular degeneration (e.g., age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti’s crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher’s syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g., juvenile retinoschisis), Stargardt disease, ophthalmoplegia, and the like. In some embodiments, the ophthalmological disease or disorder (e.g., retinal disease or disorder) is selected from macular degeneration (e.g., age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti’s crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher’s syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g., juvenile retinoschisis), Stargardt disease, ophthalmoplegia, and the like. In some embodiments, the ophthalmological disease or disorder (e.g., retinal disease or disorder) is selected from macular degeneration (e.g., age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti’s crystalline dystrophy, retinoblastoma, retinopathy of prematurity, Usher’s syndrome, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g., juvenile retinoschisis), Stargardt disease, and the like. Viral Infections Stress granules often form during viral illnesses, as viral infections often involve hijacking the cellular reproductive machinery toward production of viral proteins. In this case, inhibitors of stress granules can be useful for interfering with viral function. Other viruses appear to inhibit SG formation to prevent the cell from mobilizing a stress response. In such a case, an inducer of stress granules can interfere with viral activity and help combat viral infections (e.g., Salubrinal, an eIF2a phosphatase inhibitor and stress granule inducer). Two viruses for which SG biology has been investigated include West Nile virus and respiratory syncytial virus (RSV). Therefore, use of compounds that may inhibit formation of protein inclusions and stress granules, including compounds of Formula (I), (II), (III), or (IV), may be useful for the prevention or treatment of a viral infection. Exemplary viruses include, but are not limited to, West Nile virus, respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), hepatitis A, B, C, and D viruses, herpes viruses, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV, Ebola virus, and the like. In some embodiments, the viral infection is caused by a virus selected from the group consisting of West Nile virus, respiratory syncytial virus (RSV), herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV-1, HIV-2, Ebola virus, and any combination thereof. In some embodiments, the viral infection is caused by a virus selected from the group consisting of herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, HIV-1, HIV-2, Ebola virus, and any combination thereof. In some embodiments, the viral infection is HIV-1 or HIV-2. Definitions Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed compositions and methods, because the scope of the disclosure is limited only by the claims. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein, the terms “compounds” and “agent” are used interchangeably to refer to the inhibitors / antagonists / agonists of the compounds disclosed herein. In some embodiments, the compounds are small organic or inorganic molecules, e.g., with molecular weights less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu. In some embodiments, one class of small organic or inorganic molecules are non-peptidyl, e.g., containing 2, 1, or no peptide or saccharide linkages. Unless otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages may mean ±1%, ±2%, ±5%, or ±10%. The singular terms “a,” “an,” and “the” refer to one or to more than one, unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. As used herein, the term “administer” refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced. A compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration. The terms “decrease”, “reduced”, “reduction” , “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount. In some embodiments, the terms “reduced”, “reduction”, “decrease” or “inhibit” mean a decrease by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absent level as compared to a reference sample), or any decrease between 1- 100%, e.g., 10-100% as compared to a reference level. The terms “increased”, ”increase”, “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount. In some embodiments, the terms “increased”, “increase”, “enhance” or “activate” mean an increase by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g., absent level as compared to a reference sample), or any increase between 1-100%, e.g., 10-100% as compared to a reference level. The terms “treat”, “treating”, and “treatment”, as used herein, refer to a method of alleviating, ameliorating, inhibiting, reversing, or slowing down or stopping the progression, aggravation or deterioration of a disease or disorder or its symptoms or associated conditions. In some embodiments, at least one symptom or associated conditions of a disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%. As used herein, a “therapeutically effective amount” or an “effective amount” of a compound or combination refers to an amount of the compound or combination which is effective, upon single or multiple dose administration(s) to a subject, in treating a disease or disorder (e.g., a disorder as described herein) in a subject, or in curing, alleviating, relieving or improving a subject with a disease or disorder (e.g., a disorder as described herein) beyond that expected in the absence of such treatment. Determination of a therapeutically effective amount or an effective amount is well within the capability of those skilled in the art. Generally, a therapeutically effective amount or an effective amount can vary with the subject’s history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents. As used herein, a “subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents. In some embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, “patient” and “subject” are used interchangeably herein. The terms, “patient” and “subject” are used interchangeably herein. As used herein, the terms “modulator of stress granule” and “stress granule modulator” refer to compounds and compositions of Formula (I), (II), or (III) that modulate the formation or disaggregation of stress granules. The term “TDP-43 inclusion” as used herein refers to protein aggregates that comprise TDP-43 proteins. The TDP-43 protein in the inclusion can be wild-type or a mutant form of TDP-43. As used herein, the terms “modulator of TDP-43 inclusion” and “TDP-43 inclusion modulator” refer to compounds and compositions of Formula (I), (II), or (III) that modulate the formation or disaggregation of cytoplasmic TDP-43 inclusions. As used herein, the terms “modulator of tau aggregate” and “tau aggregate modulator” refer to compounds and compositions of Formula (I), (II), or (III) that modulate the formation or disaggregation of tau aggregates. Selected Chemical Definitions At various places in the present specification, substituents of compounds disclosed herein are recited in groups or in ranges. It is specifically intended that the compounds disclosed herein include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl and hexyl. For compounds disclosed herein in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of compounds disclosed herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the compounds disclosed herein which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. If a compound of the compounds disclosed herein is depicted in the form of a chemical name and as a formula, in case of any discrepancy, the formula shall prevail. The symbol , whether utilized as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the structure (e.g., molecule or solid support). The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, purification, or use for one or more of the purposes disclosed herein. Suitable substituents for an optionally substituted alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group include halogen, =O, —CN, —ORcc, —NRddRee, —S(O)kkRcc, — NRccS(O)2Rcc, —S(O)2NRddRee, —C(=O)ORcc, —OC(=O)ORcc, —OC(=O)Rcc, — OC(=S)ORcc, —C(=S)ORcc, —O(C=S) Rcc, —C(=O)NRddRee, —NRccC(=O) Rcc, — C(=S)NRddRee, —NRccC(=S)Rcc, —NRcc(C=O)ORcc, —O(C=O)NRddRee, —NRcc(C=S)ORcc, —O(C=S)NRddRee, —NRcc(C=O)NRddRee, —NRcc(C=S)NRddRee, —C(=S)Rcc, —C(=O)Rcc, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C9heteroalkynyl, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6- heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more of halogen, ORcc, —NO2, —CN, —NRccC(=O)W, —NRddRee, —S(O)kRcc, —C(=O)ORcc, — C(=O)NRddRee, —C(=O)Rcc, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, and wherein Rccis hydrogen, hydroxy, C1-C6alkyl, C1-C6heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6- heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6- heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which may be optionally substituted with one or more of halogen, hydroxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Rddand Reeare each independently selected from hydrogen, C1-C6alkyl, or C1-C6heteroalkyl; and k is 0, 1 or 2. The compounds disclosed herein are not intended to be limited in any manner by the above exemplary listing of substituents. As used herein, the term “optional substituent” refers to any of the suitable substituents for an alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group, including: halogen, =O, —CN, —ORcc, —NRddRee, —S(O)kkRcc, —NRccS(O)2Rcc, —S(O)2NRddRee, — C(=O)ORcc, —OC(=O)ORcc, —OC(=O)Rcc, —OC(=S)ORcc, —C(=S)ORcc, —O(C=S) Rcc, —C(=O)NRddRee, —NRccC(=O) Rcc, —C(=S)NRddRee, —NRccC(=S)Rcc, — NRcc(C=O)ORcc, —O(C=O)NRddRee, —NRcc(C=S)ORcc, —O(C=S)NRddRee, — NRcc(C=O)NRddRee, —NRcc(C=S)NRddRee, —C(=S)Rcc, —C(=O)Rcc, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C9heteroalkynyl, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1- C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-a lkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more of halogen, —ORcc, —NO2, —CN, —NRccC(=O)Rdd, —NRddRee, —S(O)kRcc, —C(=O)ORcc, —C(=O)NRddRee, — C(=O)Rcc, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, and wherein Rccis hydrogen, hydroxy, C1-C6alkyl, C1-C6heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)- carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)- heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6- alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which may be optionally substituted with one or more of halogen, hydroxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Rddand Reeare each independently selected from hydrogen, C1-C6alkyl, or C1-C6heteroalkyl; and k is 0, 1 or 2. The compounds disclosed herein are not intended to be limited in any manner by the above exemplary listing of substituents. As used herein, “alkyl” refers to a radical of a straight–chain or branched, saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C24alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6alkyl”). Examples of C1-C6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert– butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is unsubstituted C1–10alkyl (e.g., –CH3). In some embodiments, the alkyl group is substituted C1–6alkyl. As used herein, the term "alkylene” refers to an alkyl group with one additional open valence, i.e., a bivalent group. Exemplary alkylene groups include, but are not limited to -CH2CH2- and -CH2-C(CH3)-CH2-. As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C2-C24alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1– butenyl). Examples of C2-C4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2– propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2- C6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl group is unsubstituted C2–10alkenyl. In some embodiments, the alkenyl group is substituted C2–6alkenyl. As used herein, the term “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C2-C24alkenyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-C5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-C4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-C3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2-C4alkynyl groups include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl group is unsubstituted C2–10alkynyl. In some embodiments, the alkynyl group is substituted C2–6alkynyl. As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight-chain or branched, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2- O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, - NHCH2-, -C(O)NH-, -C(O)N(CH3), -C(O)N(CH2CH3)-, -C(O)N(CH2CF3)-, -S(O)-CH3, - CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like, it will be understood that the terms heteroalkyl and –CH2O or –NRCRDare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like. As used herein, the term "heteroalkylene” refers to a heteroalkyl group with one additional open valence, i.e., a bivalent group. Exemplary heteroalkylene groups include, but are not limited to: -CH2-CH2-O-CH2-, -CH2-O-,and -CH2-CH2-NH-CH2-. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ʌ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C6-C10-membered aryl, wherein the term “membered” refers to the non- hydrogen ring atoms within the moiety. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (e.g., “unsubstituted aryl”) or substituted (e.g., “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted C6-C14aryl. In some embodiments, the aryl group is substituted C6-C14aryl. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl. As used herein, “heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ʌ electrons shared in a cyclic array) having ring carbon atoms and one or more (e.g., 1–4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). A heteroaryl group may be described as, e.g., a 5-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In some embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl. Exemplary heteroaryl groups include, but are not limited to, imidazolyl, pyridinyl, and quinolinyl. As used herein, “cycloalkyl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system that is saturated or partially unsaturated, but not aromatic, and has from 3 to 14 ring carbon atoms (“C3-C14carbocyclyl”) and zero heteroatoms in the saturated or partially unsaturated, but not aromatic, ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8cycloalkyl groups include, without limitation, the aforementioned C3-C6cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10cycloalkyl groups include, without limitation, the aforementioned C3-C8cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro– 1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, the cycloalkyl group is monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is unsubstituted C3-C10cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-C10cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanyl, cyclohexenyl, cyclooctynyl, and bicyclo[4.4.0]decanyl. “Heterocycloalkyl” as used herein refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system that is saturated or partially unsaturated, but not aromatic, and has from 3 to 14 ring atoms including carbon and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur (e.g., –S–, – S(O)–, and –S(O)2–), boron, phosphorus, and silicon (“3–14 membered heterocycloalkyl”). In heterocycloalkyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocycloalkyl group can either be monocyclic (“monocyclic heterocycloalkyl”) or polycyclic (“polycyclic heterocycloalkyl”), such as bicyclic (“bicyclic heterocycloalkyl”). A heterocycloalkyl group can be a fused, bridged or spiro ring system. Bicyclic heterocycloalkyl can include one or more heteroatoms in one or both rings. A heterocycloalkyl group may be described as, e.g., a 3-7-membered heterocycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocycloalkyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocycloalkyl”) or substituted (a “substituted heterocycloalkyl”) with one or more substituents. In some embodiments, the heterocycloalkyl group is unsubstituted 3–14 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl group is substituted 3–14 membered heterocycloalkyl. In some embodiments, a heterocycloalkyl group is a 5–10 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocycloalkyl”). In some embodiments, a heterocycloalkyl group is a 5–8 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocycloalkyl”). In some embodiments, a heterocycloalkyl group is a 5–6 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocycloalkyl”). In some embodiments, the 5–6 membered heterocycloalkyl has 1–3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocycloalkyl has 1–2 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocycloalkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 3,4-dihydro-2H-pyranyl, and octahydroindolyl. As used herein, “carbocyclyl” refers to a radical of a polycyclic, partially unsaturated ring system having from 6 to 20 carbon atoms and at least one fused aryl ring. The term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a carbocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is unsubstituted 6-20 membered carbocyclyl. In some embodiments, the carbocyclyl group is a substituted 6-20 membered carbocyclyl. Exemplary carbocyclyl groups include, but are not limited to, indenyl and tetrahydronaphthyl. As used herein, “heterocyclyl” refers to a radical of a polycyclic, partially unsaturated ring system having from 5 to 20 atoms (“5-20 membered heterocyclyl”) including carbon and 1 to 6 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and wherein the polycyclic, partially unsaturated ring system has at least one aromatic ring (e.g., aryl or heteroaryl). In some embodiments, a heterocyclyl group has 5 to 14 ring atoms (“5-14 membered heterocyclyl”). The term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a heterocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is unsubstituted 5-20 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 5- 20 membered heterocyclyl. Exemplary heterocyclyl groups include, but are not limited to, 1,2,3,4-tetrahydroquinolyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 1,4,6,7- tetrahydropyrano[4,3-b]pyrrole, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 5,6,7,8- tetrahydroquinolinyl. As used herein, “cyano” refers to the radical –CN. As used herein, “halo” or “halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. As used herein, “haloalkyl” can include alkyl structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” includes haloalkyl groups in which the halo is fluorine (e.g., -C1-C6alkyl-CF3, -C1-C6alkyl- C2F). Non-limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluoromethyl, and fluoroisopropyl. As used herein, “hydroxy” refers to the radical –OH. As used herein, “nitro” refers to –NO2. As used herein, “oxo” (=O) refers to a carbonyl, in which both bonds from the oxygen are connected to the same atom. For example, a carbon atom substituted with oxo forms a carbonyl group C=O.

[0027] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carbocyclyl, or heterocyclyl groups. Such so-called ringforming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring -forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring -forming substituents are attached to non-adjacent members of the base structure.

[0028] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC); or preferred isomers can be prepared by asymmetric syntheses. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0029] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In some embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In some embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In some embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound. In some embodiments, the active ingredient can be formulated with little or no excipient or carrier. Compound disclosed herein may also comprise one or more isotopic substitutions. Isotopes include those atoms having the same atomic number but different mass numbers. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Further, unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least about 45% incorporation of deuterium). One or more constituent atoms of the compounds of the present disclosure can be replaced or substituted with isotopes of the atoms in non-natural abundance. In some embodiments, the compound comprises one or more deuterium atoms. For example, one or more hydrogen atoms in a compound disclosed herein can be replaced or substituted by deuterium. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to inhibit the formation of TDP-43 inclusions), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound. In general, the compounds of the present disclosure may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. As used herein, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted. Pharmaceutical Compositions and Routes of Administration Pharmaceutical compositions containing compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) can be used to treat or ameliorate a disorder described herein, for example, a neurodegenerative disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection. The amount and concentration of compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions. While it is possible for a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to be administered alone, it is preferable to administer the compound as a pharmaceutical composition, where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers. Compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) may be formulated for administration in any convenient way for use in human or veterinary medicine. In some embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, the compounds of the present disclosure or the pharmaceutical compositions of the present disclosure are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art. Thus, another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising an effective amount of one or more of the compounds disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof), formulated together with one or more pharmaceutically acceptable carriers, additives, or diluents. The pharmaceutical compositions disclosed herein may be specially formulated for administration in solid or liquid form. The pharmaceutical compositions disclosed herein may be administered to a subject by various routes of administration including, but not limited to: oral administration; parenteral administration; topical application; intravaginally or intrarectally, sublingually; ocularly; transdermally; transmucosally; nasally; or intrathecally. Additionally, compounds disclosed herein can be implanted into a patient or injected using a drug delivery system. The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) which is effective for producing some desired therapeutic effect (e.g., by inhibiting TDP-43 inclusions, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment).

[0030] The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0031] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0032] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to: sugars; starches; cellulose; powdered tragacanth; malt; gelatin; talc; excipients; oils; glycols; polyols; esters; agar; buffering agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; cyclodextrins; and other nontoxic compatible substances employed in pharmaceutical formulations.

[0033] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure.

[0034] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0035] Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0036] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0037] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges, powders, granules, or as a solution or a suspension. In solid dosage forms of the disclosure for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, including, but not limited to: fillers or extenders; binders; humectants; disintegrating agents; solution retarding agents; absorption accelerators; wetting agents; absorbents; lubricants; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0038] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebrospinal, and intrastemal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection.

[0039] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0040] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions disclosed herein include water, ethanol, polyols, and suitable mixtures thereof, vegetable oils, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0041] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0042] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. Dosages Actual dosage levels of the active ingredients in the pharmaceutical compositions disclosed herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are preferred. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50(i.e., the concentration of the therapeutic which achieves a half- maximal inhibition of symptoms) as determined in cell culture. Levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. Generally, the compositions are administered so that a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), or (IV), or subformulas thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) is given at an effective dose. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen. The dosing schedule can vary depending on a number of clinical factors, such as the subject's sensitivity to the drugs. The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present disclosure contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated. EXAMPLES Examples are provided below to facilitate a more complete understanding of the compounds and methods disclosed herein. The following examples illustrate exemplary modes of making and practicing the compounds and methods disclosed herein. However, the scope of the disclosure is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. General. All oxygen or moisture sensitive reactions were carried out under N2atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2prior to use. All reagents and solvents were purchased from commercial vendors and used as received, or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz1H, 75 MHz13C) or Varian (400 MHz1H, 75 MHz13C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant (s) in Hz). Unless otherwise indicated NMR data were collected at 25 ºC. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid Chromatography / Mass Spectrometry (LCMS) was performed on Agilent 1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO4) stain followed by heating.

[0043] Table 2: Abbreviations

[0044] EXAMPLE 1: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1- methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)thiophen-2-yl)methanone (Compound 103) Step 14-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethoxy)phenyl)piperidine A mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethoxy)phenyl)piperidine-1-carboxylate (1.00 g, 2.10 mmol) in HCl (10 mL, 2M in EtOAc) was stirred at 25°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness to afford the desired product (0.95 g, 95.2% yield) as a yellow solid. Step 21-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethoxy)phenyl)piperidine To a mixture of compound 2 (950 mg, 2.56 mmol) in DCM (90 mL) were added NaBH(OAc)3(4.88 g, 23.03 mmol), HCHO (831 mg, 10.24 mmol, 37 wt% in H2O) and Na2SO4(182 mg, 1.28 mmol), then it was stirred at 25°C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (DCM / MeOH=10 / 1) to afford the desired product (850 mg, 77.6% yield) was obtained as a yellow solid. Step 3 tert-butyl (S)-(1-(3-methyl-5-(4-(1-methylpiperidin-4-yl)-2- (trifluoromethoxy)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 3 (400 mg, 1.04 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) were added compound 4 (364 mg, 0.93 mmol), K3PO4(661 mg, 3.11 mmol) and Pd(dppf)Cl2*DCM (127 mg, 0.16 mmol), then it was stirred at 95°C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (DCM / MeOH=10 / 1) to afford the desired product (160 mg, 25.8% yield) was obtained as yellow oil. Step 4 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-methylpiperidin-4-yl)-2- (trifluoromethoxy)phenyl)thiophen-2-yl)methanone A mixture of compound 5 (160 mg, 0.28 mmol) in HCl (3 mL, 2M in EtOAc) was stirred at 25°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford the desired product (Compound 103; 27.6 mg, 20.9% yield) was obtained as a white solid. MS (ESI): mass calc’d. for C23H28F3N3O2S 468.20, m / z found 468.2 [M+H]+.1H NMR (400 MHz, MeOD) 7.75 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 4.03 - 3.93 (m, 2H), 3.86 - 3.73 (m, 2H), 3.72 - 3.60 (m, 3H), 3.22 - 3.10 (m, 2H), 3.03 - 2.95 (m, 1H), 2.92 (s, 3H), 2.49 - 2.39 (m, 1H), 2.36 (s, 3H), 2.19 - 2.08 (m, 3H), 2.04 - 1.92 (m, 2H). EXAMPLE 2: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(5-(1- methylpiperidin-4-yl)pyridin-2-yl)thiophen-2-yl)methanone (Compound 104) Step 1 Synthesis of tert-butyl (S)-(1-(5-(5-chloropyridin-2-yl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (390 mg, 1 mmol) in DMF(10 mL) were added (5-chloropyridin-2-yl)boronic acid (157.6 mg, 1 mmol), Cs2CO3(979.2 mg, 3 mmol), Pd(dppf)Cl2DCM (163.5 mg, 0.2 mmol) and CuCl (99 mg, 1 mmol). The mixture was stirred at 100 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography PE:EA=1:1 to give tert-butyl (S)-(1-(5-(5- chloropyridin-2-yl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (85 mg, 19.11% yield) as a yellow solid. LCMS (ESI) calc’d for C20H25ClN3O3S+ [M + H]+ m / z 422.13, found 422. Step 2 Synthesis of tert-butyl (S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-[3,4'- bipyridin]-6-yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-(5-chloropyridin-2-yl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (430 mg, 1.02 mmol) in dioxane / H2O = 8:1 (18 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (227.4 mg, 1.02 mmol), K3PO4(649 mg, 3.06 mmol) and Pd(dppf)Cl2DCM (166.3 mg, 0.2 mmol). The mixture was stirred at 95 ºC under N2for 16h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH:EA=2:1) to give tert-butyl (S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'- tetrahydro-[3,4'-bipyridin]-6-yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 32.5 % yield) as a brown solid. LCMS (ESI) calc’d for C26H34N4O3S+ [M + H]+ m / z 482.24, found 483. Step 3 Synthesis of tert-butyl (S)-(1-(3-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2- yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate A solution of tert-butyl (S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-[3,4'- bipyridin]-6-yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (448 mg, 0.88 mmol) and PtO2 (19.9 mg, 0.088 mmol) in EA(20 mL) was stirred at rt under H2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(1-(3-methyl-5-(5-(1- methylpiperidin-4-yl)pyridin-2-yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (380 mg, 80.3% yield) as a yellow oil. LCMS (ESI) calc’d for C28H40N3O4S+ [M + H]+ m / z 514.28, found 514. Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(5-(1-methylpiperidin-4- yl)pyridin-2-yl)thiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(3-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2- yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (220 mg, 0.45 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3- aminopyrrolidin-1-yl)(3-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)thiophen-2- yl)methanone (Compound 104; 34.7 mg, 19.7% yield) as a yellow solid. LCMS (ESI) calc’d for C22H30N3O2S+ [M + H]+ m / z 400.21, found 400.1H NMR (400 MHz, MeOD) δ 8.89 (d, J = 2.1 Hz, 2H), 8.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 4.04 – 3.95 (m, 2H), 3.84 (dt, J = 11.7, 7.5 Hz, 1H), 3.75 (ddd, J = 17.7, 10.6, 5.8 Hz, 2H), 3.66 (s, 2H), 3.22 (dd, J = 8.1, 3.1 Hz, 1H), 3.20 – 3.13 (m, 1H), 2.96 (d, J = 15.5 Hz, 3H), 2.45 (td, J = 14.0, 7.5 Hz, 1H), 2.37 (s, 3H), 2.17 (ddt, J = 22.6, 14.6, 8.5 Hz, 5H). EXAMPLE 3: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(6-(1- methylpiperidin-4-yl)pyridin-3-yl)thiophen-2-yl)methanone (Compound 108) Step 1 tert-butyl(S)-(1-(5-(6-chloropyridin-3-yl)-3-methylthiophene-2-carbonyl)pyrrolidin-3- yl)carbamate To the solution of (6-chloropyridin-3-yl)boranediol (230 mg, 1.4616 mmol) in EtOH / DME=1:1 (8 mL) were added tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (569 mg, 1.4616 mmol), Na2CO3(464.8 mg, 4.3848 mmol) and Pd(PPh3)4(337.8 mg, 0.2923 mmol). The mixture was stirred under N2at 95 ºC for 16 h. After the reaction, the mixture was cooled to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (520 mg, 75.89% yield) as a yellow solid. LCMS (ESI) calc’d for C11H14ClNO4S+ [M + H]+ m / z 422, found 422. Step 2 tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-(2,4'-bipyridin)-5- yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl(S)-(1-(5-(6-chloropyridin-3-yl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (520 mg, 1.2324 mmol) in dioxane / H2O=8:1 (18 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine (412.5 mg, 1.8486 mmol), K3PO4(915.6 mg, 4.3134 mmol) and Pd(dppf)Cl2DCM (201.1 mg, 0.2464 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was cooled to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (210 mg, 31.78% yield) as a yellow solid. LCMS (ESI) calc’d for C26H35N4O3S+ [M + H]+ m / z 483, found 483. Step 3 tert-butyl(S)-(1-(3-methyl-5-(6-(1-methylpiperidin-4-yl)pyridin-3-yl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-(2,4'- bipyridin)-5-yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (210 mg, 0.4351 mmol) in EtOAc (5 mL) was added PtO2(19.7 mg). The mixture was stirred at rt under H2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure to afford the desired product (200 mg, 85.36% yield) as a yellow solid. LCMS (ESI) calc’d for C26H37N4O3S+ [M + H]+ m / z 485, found 485. Step 4 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(6-(1-methylpiperidin-4-yl)pyridin-3- yl)thiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(3-methyl-5-(6-(1-methylpiperidin-4-yl)pyridin-3- yl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (100 mg, 0.2063 mmol) in EtOAc (2 mL) was added HCl (5 ml, 2M in EtOAc). The mixture was stirred at rt for 16 h. After the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the desired product (Compound 108; 15 mg, 17.01% yield) as a yellow solid. LCMS (ESI) calc’d for C21H29N4OS+ [M + H]+ m / z 385, found 385.1H NMR (400 MHz, MeOD) δ 8.82 (d, J = 2.0 Hz, 1H), 8.06 – 8.05 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 4.05 – 3.98 (m, 2H), 3.88 – 3.77 (m, 2H), 3.74 – 3.63 (m, 3H), 3.25 – 3.05 (m, 3H), 2.96 (d, J = 8.0 Hz, 3H), 2.47 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H), 2.16 – 2.10 (m, 5H). EXAMPLE 4: Synthesis of (S)-(3-allyl-5-(4-(1-isopropylpiperidin-4-yl)phenyl)thiophen- 2-yl)(3-aminopyrrolidin-1-yl)methanone (Compound 109) Step 1 tert-butyl(S)-(1-(3-allyl-5-(4-(1-isopropylpiperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(3-bromo-5-(4-(1-isopropylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (650 mg, 1.1273 mmol) in dioxane / H2O=8:1 (18 mL) were added 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2- dioxaborolane (189.4 mg, 1.1273 mmol), K3PO4(717.8 mg, 3.3819 mmol) and Pd(dppf)Cl2DCM (91.9 mg, 0.1127 mmol).The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was cooled to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (390 mg, 57.90% yield) as a yellow solid. LCMS (ESI) calc’d for C31H44N3O3S+ [M + H]+ m / z 538, found 538. Step 2 (S)-(3-allyl-5-(4-(1-isopropylpiperidin-4-yl)phenyl)thiophen-2-yl)(3-aminopyrrolidin- 1-yl)methanone To the solution of tert-butyl(S)-(1-(3-allyl-5-(4-(1-isopropylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 0.2789 mmol) in EtOAc (2 mL) was added 2M HCl in EtOAc (5 mL).The mixture was stirred at rt for 16 h. After the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the desired product (Compound 109; 30 mg, 22.12% yield) as a yellow solid. LCMS (ESI) calc’d for C26H36N3OS + [M + H]+ m / z 438, found 438.1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 6.02 (m, 1H), 5.21 – 5.07 (m, 2H), 4.06 – 3.94 (m, 2H), 3.88 – 3.65 (m, 3H), 3.58 (m, 3H), 3.52 (d, J = 6.4 Hz, 2H), 3.23 (m, 2H), 3.03 – 2.91 (m, 1H), 2.45 (m, 1H), 2.23 – 1.97 (m, 5H), 1.43 (d, J = 6.8 Hz, 6H). EXAMPLE 5: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-isopropylpiperidin-4- yl)phenyl)-3-propylthiophen-2-yl)methanone (Compound 110) Step 1 tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3-propylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(3-allyl-5-(4-(1-isopropylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 0.2789 mmol) in EtOAc (5 mL) was added PtO2(12.7 mg). The mixture was stirred at rt under H2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed and the residue was purified by flash chromatography to give the desired product as a yellow solid. MS (ESI): mass calc’d for C31H45N3O3S 539, m / z found 540 [M+H]+. Step 2 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- propylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- propylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 0.2779 mmol) in EtOAc (2 mL) was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 110; 30 mg, 22.09% yield) as a yellow solid. MS (ESI): mass calc’d C26H38N3OS 440, m / z found 440 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.68 – 7.60 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 4.05 – 3.95 (m, 2H), 3.89 – 3.65 (m, 3H), 3.58 (m, 3H), 3.23 (m, 2H), 3.02 – 2.92 (m, 1H), 2.75 – 2.67 (m, 2H), 2.46 (m, 1H), 2.24 – 1.97 (m, 5H), 1.72 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H), 0.99 (t, J = 7.2 Hz, 3H).

[0045] EXAMPLE 6: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(3-methoxy-4-(1- methylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 111) Step 14-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6- tetrahydropyridine A solution of tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (580 mg, 1.4 mmol) in 4 mL EtOAc was added HCl (5 mL, 2M in EA). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. the resulting mixture was concentrated under reduced pressure to give 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (509 mg, 110% yield) as a yellow oil. LCMS (ESI) calc’d for C18H27BNO3+ [M + H]+ m / z 316.21, found 316. Step 24-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl- 1,2,3,6-tetrahydropyridine To a solution of 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-1,2,3,6-tetrahydropyridine (1100 mg, 3.5 mmol) in DCM (20 mL) was added HCHO (314.4 mg, 10.5 mmol, 37 wt% in H2O) and NaBH(OAc)3(440 mg, 10.5 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The residue was concentrated under reduced pressure to give 4-(2- methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6- tetrahydropyridine (900 mg, 74.4% yield) as a yellow solid. LCMS (ESI) calc’d for C19H29BNO3+ [M + H]+ m / z 330.23, found 330. Step 3 (S)-(1-(5-(3-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (800 mg, 2.05 mmol) in dioxane / H2O=8:1 (18 mL) were added 4-(2- methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6- tetrahydropyridine (676.6 mg, 2.05 mmol), K3PO4(1308.6 mg, 6.16 mmol) and Pd(dppf)Cl2DCM (335.4 mg, 0.41 mmol). The mixture was stirred at 95 ºC under N2for 16h. After cooling rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using MeOH:EA=1:10 as eluent to afford tert- butyl (S)-(1-(5-(3-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (448 mg, 40.5 % yield) as a yellow solid. LCMS (ESI) calc’d for C28H37N3O4S+ [M + H]+ m / z 511.25, found 512. Step 4 tert-butyl (S)-(1-(5-(3-methoxy-4-(1-methylpiperidin-4-yl)phenyl)-3-methylthiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate A solution of tert-butyl (S)-(1-(5-(3-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridin- 4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (448 mg, 0.88 mmol) and PtO2(19.9 mg, 0.088 mmol) in EtOAc (20 mL) was stirred at rt under H2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(1-(5-(3- methoxy-4-(1-methylpiperidin-4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3- yl)carbamate (380 mg, 80.3% Yield) as a yellow oil. LCMS (ESI) calc’d for C28H39N3O4S+ [M + H]+ m / z 513.27, found 514. Step 5 (S)-(3-aminopyrrolidin-1-yl)(5-(3-methoxy-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone A solution of tert-butyl (S)-(1-(5-(3-methoxy-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (380 mg, 0.74 mmol) in 4 mL EtOAc was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was concentrated under reduced pressure to give (S)-(3-aminopyrrolidin-1-yl)(5-(3-methoxy-4-(1- methylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 111; 350 mg) as a yellow solid. LCMS (ESI) calc’d for C23H32N3O2S+ [M + H]+m / z 414.22, found 414.1H NMR (400 MHz, MeOD) δ 7.30 (s, 1H), 7.24 (s, 2H), 7.22 (s, 1H), 4.01 (t, J = 7.2 Hz, 2H), 3.94 (d, J = 7.1 Hz, 3H), 3.87 (dt, J = 9.2, 6.2 Hz, 1H), 3.83 – 3.69 (m, 2H), 3.63 (d, J = 12.3 Hz, 2H), 3.25 – 3.12 (m, 2H), 2.93 (s, 3H), 2.52 – 2.42 (m, 1H), 2.38 (s, 3H), 2.23 – 1.92 (m, 6H).

[0046] EXAMPLE 7: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1- methylpiperidin-4-yl)-3-(trifluoromethoxy)phenyl)thiophen-2-yl)methanone (Compound 112) Step 14-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)phenyl)piperidine A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)phenyl)piperidine-1-carboxylate (470 mg, 1.00 mmol) in HCl (5 mL, 2M in EtOAc) was stirred at 25°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness to afford the desired product (445 mg, 96.4% yield) as a yellow solid. Step 21-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)phenyl)piperidine To a mixture of compound 2 (445 mg, 1.20 mmol) in DCM (45 mL) was added NaBH(OAc)3(2.29 g, 10.79 mmol), HCHO (389 mg, 4.80 mmol) and Na2SO4(85 mg, 0.60 mmol), then it was stirred at 25°C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. Then it was diluted with ethyl acetate and filtrated. The filtrate was concentrated to dryness to afford the desired product (450 mg, 87.7% yield) as yellow oil. Step 3 tert-butyl (S)-(1-(3-methyl-5-(4-(1-methylpiperidin-4-yl)-3- (trifluoromethoxy)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 3 (450 mg, 1.17 mmol) in 1,4-dioxane (10 mL) and H2O (1.2 mL) were added compound 4 (409 mg, 1.05 mmol), K3PO4(620 mg, 2.92 mmol) and Pd(dppf)Cl2*DCM (143 mg, 0.18 mmol), then it was stirred at 95°C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM = 8%) to afford the desired product (280 mg, 38.0% yield) as a black solid. Step 4 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-methylpiperidin-4-yl)-3- (trifluoromethoxy)phenyl)thiophen-2-yl)methanone A solution of compound 5 (280 mg, 0.49 mmol) in HCl (3 mL, 2M in EtOAc) was stirred at 25°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford the desired product (Compound 112; 22.4 mg, 9.6% yield) as a white solid. MS (ESI): mass calc’d. for C23H29F3N3O2S 468.20, m / z found 468.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.65 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 3.82 - 3.72 (m, 2H), 3.68 - 3.54 (m, 2H), 3.32 (s, 1H), 3.10 - 3.00 (m, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.26 - 2.15 (m, 3H), 1.92 - 1.82 (m, 3H), 1.81 - 1.72 (m, 2H).

[0047] EXAMPLE 8: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-isopropylpiperidin-4- yl)phenyl)-3-vinylthiophen-2-yl)methanone (Compound 117) Step 1 tert-butyl(S)-(1-(3-bromo-5-(4-(1-isopropylpiperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(3,5-dibromothiophene-2-carbonyl)pyrrolidin-3- yl)carbamate (1 g, 0.0022 mol) in dioxane / H2O=8:1 (18 mL) were added 1-isopropyl-4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.72 g, 0.0022 mmol), K3PO4(1.4 g, 0.0066 mol) and Pd(dppf)Cl2DCM (0.18 g, 0.0002 mol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (0.8 g, 54.55% yield) as a yellow solid. MS (ESI): mass calc’d for C28H39BrN3O3S 576, m / z found 576 [M+H]+. Step 2 tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3-vinylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(3-bromo-5-(4-(1-isopropylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (800 mg, 1.3875 mmol) in 10 mL of toluene and 1 mL of H2O were added Potassium vinyltrifluoroborate (205.98 mg, 1.5262 mmol), t-BuOK (504.54 mg, 4.1625 mmol) and Pd(dppf)Cl2DCM (113.22 mg, 0.1387 mmol). The mixture was stirred at 95°C under N2for 16 hours. After the reaction, the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product (500 mg, 61.69% yield) as a yellow oil. MS (ESI): mass calc’d for C30H42N3O3S 524, m / z found 524 [M+H]+. Step 3 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3-vinylthiophen- 2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- vinylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (140 mg, 0.2673 mmol) in EtOAc (2 mL) was added HCl (4 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 117; 20 mg, 15.90% yield) as a white solid. MS (ESI): mass calc’d for C25H34N3OS 424, m / z found 424 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.72 – 7.64 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 6.84 (m, 1H), 5.88 (m, 1H), 5.44 (m, 1H), 3.99 (d, J = 10.8 Hz, 2H), 3.86 – 3.64 (m, 3H), 3.59 (m, 3H), 3.23 (m, 2H), 2.98 (m, 1H), 2.46 (m, 1H), 2.24 – 1.97 (m, 5H), 1.43 (d, J = 6.8 Hz, 6H).

[0048] EXAMPLE 9: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-ethyl-5-(4-(1- isopropylpiperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 118) Step 1 tert-butyl(S)-(1-(3-ethyl-5-(4-(1-isopropylpiperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- vinylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (350 mg, 0.6683 mmol) in EtOAc (5 mL) was added PtO2(30.35 mg). The mixture was stirred at rt under H2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The residue was purified by flash chromatography to give the desired product (300 mg, 76.85% yield) as a yellow solid. MS (ESI): mass calc’d for C30H44N3O3S 526, m / z found 526 [M+H]+. Step 2 (S)-(3-aminopyrrolidin-1-yl)(3-ethyl-5-(4-(1-isopropylpiperidin-4-yl)phenyl)thiophen- 2-yl)methanone To the solution of tert-butyl (S)-(1-(3-ethyl-5-(4-(1-isopropylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (300 mg, 0.5706 mmol) in EtOAc (2 mL) was added 2M HCl in EtOAc (5 ml).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The residue was purified by prep-HPLC to give the desired product (Compound 118; 30 mg, 11.11% yield) as a yellow solid. MS (ESI): mass calc’d for C25H36N3OS 426, m / z found 426 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.68 – 7.63 (m, 2H), 7.37 (s, 1H), 7.35 (d, J = 3.6 Hz, 2H), 4.04 – 3.91 (m, 2H), 3.88 – 3.72 (m, 2H), 3.69 – 3.54 (m, 4H), 3.23 (m, 2H), 2.97 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.44 (m, 1H), 2.22 – 2.02 (m, 5H), 1.43 (d, J = 6.8 Hz, 6H), 1.29 (t, J = 7.6 Hz, 3H). EXAMPLE 10: Synthesis of ((S)-3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-((tetrahydro- 2H-pyran-2-yl)methyl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 119) Step 1 (4-(4-bromophenyl)piperidin-1-yl)(tetrahydro-2H-pyran-2-yl)methanone To a mixture of 4-(4-bromophenyl)piperidine (600 mg, 2.50 mmol) in DMF (10 mL) were added oxane-2-carboxylic acid (390 mg, 3.00 mmol), DIEA (1.29 g, 9.99 mmol) and HATU (1.14 g, 3.00 mmol), then it was stirred at 50°C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (15 mL * 3). The combined organic phases were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography on silica gel (EA / PE=20%) to give the desired product (920 mg, 94.1% yield) as a yellow oil. Step 24-(4-bromophenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)piperidine A mixture of compound 3 (920 mg, 2.6117 mmol) in THF (9 mL) was added BH3(144.48 mg, 10.446 mmol), then the mixture was stirred at 75°C for 4 hours under N2atmosphere. LCMS showed the reaction was completed. After the reaction was cooled in an ice bath, methanol (5 mL) was added cautiously. HCl (6 M, 8 mL) was added fast dropwise, and the mixture was heated to reflux for 30 minutes. The volatiles were then concentrated in vacuo, and the resulting mixture was cooled in an ice bath and 50% aqueous NaOH (10 mL) was added (pH>10). The mixture was then diluted with water and extracted with diethyl ether (50 mL * 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (EA / PE=20%~30%) to afford compound 4 (830 mg, 86.4% yield) as colorless oil. Step 31-((tetrahydro-2H-pyran-2-yl)methyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a mixture of compound 4 (830 mg, 2.45 mmol) in 1,4-dioxane (15 mL) were added B2Pin2(748 mg, 2.94 mmol), KOAc (722 mg, 7.36 mmol) and Pd(dppf)Cl2DCM (301 mg, 0.37 mmol), then it was stirred at 100°C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (DCM / MeOH=10 / 1) to afford compound 5 (1.00 g, 84.6% yield) as black oil. Step 4 tert-butyl ((3S)-1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-2-yl)methyl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 5 (500 mg, 1.30 mmol) in 1,4-dioxane (14 mL) and H2O (2 mL) was added compound 6 (404 mg, 1.04 mmol), K3PO4(826 mg, 3.89 mmol) and Pd(dppf)Cl2*DCM (159 mg, 0.19 mmol), then it was stirred at 95°C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM=5%) to afford compound 7 (280 mg, 34.2%) as a yellow solid. Step 5 ((S)-3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-2- yl)methyl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone A mixture of compound 7 (140 mg, 0.25 mmol) in HCl / EtOAc (2 mL) was stirred at 25°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford Compound 119 (109.3 mg, 94.8% yield) as a white solid. LCMS (ESI): mass calc’d. for C27H37N3O2S 467.26, m / z found 468.3 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.4 Hz, 2H), 7.41 - 7.29 (m, 2H), 7.24 (s, 1H), 4.06 - 3.95 (m, 3H), 3.83 (s, 3H), 3.75 - 3.63 (m, 3H), 3.57 - 3.48 (m, 1H), 3.26 - 3.03 (m, 4H), 2.98 - 2.85 (m, 1H), 2.49 - 2.39 (m, 1H), 2.35 (s, 3H), 2.18 - 2.05 (m, 4H), 2.03 - 1.88 (m, 2H), 1.68 - 1.55 (m, 4H), 1.36 - 1.26 (m, 1H). EXAMPLE 11: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(2-chloro-4-(1- methylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 120) Step 14-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6- tetrahydropyridine A mixture of tert-butyl 4-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.43 mmol) in HCl / EtOAc (6 mL) was stirred at 25°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness to afford the desired product (560 mg, 86.0% yield) as a yellow solid. Step 24-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6- tetrahydropyridine To a mixture of compound 2 (560 mg, 1.75 mmol) in DCM (50 mL) was added NaBH(OAc)3(3.34 g, 15.77 mmol), HCHO (569 mg, 7.01 mmol, 37 wt% in H2O ) and Na2SO4(124 mg, 0.88 mmol), then it was stirred at 25°C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EA / MeOH=5 / 1) to afford the desired product (480 mg, 73.9% yield) as a yellow solid. Step 3 tert-butyl (S)-(1-(5-(2-chloro-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 3 (480 mg, 1.44 mmol) in 1,4-dioxane (16 mL) and H2O (2 mL) were added compound 4 (504 mg, 1.29 mmol), K3PO4(916 mg, 4.32 mmol) and Pd(dppf)Cl2*DCM (176 mg, 0.22 mmol), then it was stirred at 95°C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM=5%~6%) to afford the desired product (410 mg, 49.7% yield) as a yellow solid. Step 4 tert-butyl (S)-(1-(5-(2-chloro-4-(1-methylpiperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 5 (410 mg, 0.79 mmol) in EtOAc (4 mL) was added PtO2(41 mg, 0.18 mmol), then it was stirred at 25°C for 32 hours under H2atmosphere. LCMS showed the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated to dryness to afford the desired product (390 mg, 85.3% yield) as a yellow solid. Step 5 (S)-(3-aminopyrrolidin-1-yl)(5-(2-chloro-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone A mixture of compound 6 (240 mg, 0.46 mmol) in HCl / EtOAc (3 mL) was stirred at 25°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford the desired product (Compound 120; 12.6 mg, 6.2% yield) as a white solid. MS (ESI): mass calc’d. for C22H29ClN3OS 418.17, m / z found 418.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 4.03 - 3.96 (m, 2H), 3.89 - 3.75 (m, 2H), 3.74 - 3.59 (m, 3H), 3.16 (t, J = 12 Hz, 2H), 2.94 (s, 4H), 2.50 - 2.40 (m, 1H), 2.37 (s, 3H), 2.19 - 2.10 (m, 3H), 2.07 - 1.92 (m, 2H). The following compound was prepared analogously to Compound 120:

[0049] EXAMPLE 12: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(2-(1- methylpiperidin-4-yl)pyrimidin-5-yl)thiophen-2-yl)methanone (Compound 124) Step 12-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine To a mixture of 2-(piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidine (100 mg, 0.35 mmol) in DCM (10 mL) was added NaBH(OAc)3(660 mg, 3.11 mmol), HCHO (112 mg, 1.38 mmol) and Na2SO4(25 mg, 0.17 mmol), then it was stirred at 25°C for 12 hours. After the reaction, the mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM = 0%~30%) to give the desired product (200 mg, 85.8% yield) as a white solid. Step 2 tert-butyl (S)-(1-(3-methyl-5-(2-(1-methylpiperidin-4-yl)pyrimidin-5-yl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 2 (200 mg, 0.66 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) were added compound 3 (231 mg, 0.59 mmol), K3PO4(420 mg, 1.98 mmol) and Pd(dppf)Cl2*DCM (81 mg, 0.10 mmol), then it was stirred at 95°C under N2for 16 hours. After the reaction, the mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel using MeOH / DCM = 0%~30% as eluent to afford compound 4 (100 mg, 28.1% yield) as a black solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(2-(1-methylpiperidin-4-yl)pyrimidin-5- yl)thiophen-2-yl)methanone A mixture of compound 4 (100 mg, 0.2059 mmol) in HCl / EtOAc (2 mL) was stirred at 25°C for 3 hours. The LCMS showed the reaction was completed. The mixture was concentrated to dryness and the crude product was purified by prep-HPLC to afford the desired product Compound 124 (7 mg, 8.7% yield) as a white solid. MS (ESI): mass calc’d. for C20H27N5OS 385.19, m / z found 386.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 9.01 (s, 2H), 8.52 (s, 2H), 7.45 (s, 1H), 3.95 - 3.77 (m, 3H), 3.75 - 3.67 (m, 1H), 3.57 - 3.41 (m, 3H), 3.22 - 3.13 (m, 1H), 3.05 - 2.92 (m, 2H), 2.81 - 2.75 (m, 3H), 2.37 (s, 3H), 2.35 - 2.24 (m, 3H), 2.22 - 2.11 (m, 2H), 2.05 - 1.97 (m, 1H). The following compounds are prepared analogously to the methods described in this example:

[0050] EXAMPLE 13: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(2-fluoro-4-(1- methylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 128) Step 14-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To the solution of tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate (600 mg, 1.4767 mmol) in EtOAc (2 mL) was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure to afford the desired product (500 mg, 94.30% yield) as a colorless oil. Step 24-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine To a mixture of 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine (500 mg, 1.6383 mmol) in DCM (50 mL) was added NaBH(OAc)3(3124.9 mg, 14.744 mmol), formaldehyde aqueous solution (531.3 mg, 6.5532 mmol) and Na2SO4(69.8 mg, 0.4914 mmol), then it was stirred at 25ºC for 16 hours. The LCMS showed the reaction was completed and the desired MS was found. After the reaction, the solvent was removed under reduced pressure and water was added, the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4and filtered. The solvent was removed under reduced pressure to afford the desired product (730 mg, 97.71% yield) as a colorless oil. Step 3 tert-butyl(S)-(1-(5-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 1-methylpiperidine (250 mg, 0.7832 mmol) in dioxane / H2O = 8:1 (9 mL) was added tert- butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (304.9 mg, 0.7832 mmol), K3PO4(498.7 mg, 2.3496 mmol) and Pd(dppf)Cl2DCM (127.9 mg, 0.1566 mmol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (150 mg, 34.36% yield) as a yellow solid. Step 4 (S)-(3-aminopyrrolidin-1-yl)(5-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 0.2990 mmol) in EtOAc (2 mL) was added HCl (3 mL, 2M in EtOAc).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 128; 30 mg, 22.47% yield) as a yellow solid. MS (ESI): mass calc’d for C22H29FN3OS 402, m / z found 402 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.53 (t, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.02 (m, 2H), 3.66 (m, 2H), 3.51 (m, 2H), 3.23 (s, 1H), 2.91 (d, J = 11.6 Hz, 2H), 2.49 (m, 1H), 2.23 (d, J = 2.4 Hz, 6H), 2.07 (m, 3H), 1.80 – 1.62 (m, 5H).

[0051] EXAMPLE 14: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(2-fluoro-4-(piperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 129) Step 1 tert-butyl 4-(4-bromo-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.50 g, 4.80 mmol) in 1,4-dioxane (16 mL) and H2O (4 mL) were added 1-bromo-2-fluoro-4-iodobenzene (2.17 g, 7.20 mmol), K3PO4(1.66 g, 12.00 mmol) and Pd(dppf)Cl2DCM (0.59 g, 0.70 mmol), the mixture was stirred at 80°C for under N216 hours. TLC (PE:EA=10:1) showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EA / PE=8%) to give the desired product (1.30 g, 68.7% yield) as light-yellow oil. Step 2 tert-butyl 4-(4-bromo-3-fluorophenyl)piperidine-1-carboxylate To a mixture of compound 3 (1.30 g, 3.60 mmol) in EtOAc (30 mL) was added PtO2(0.13 g, 0.50 mmol), then it was stirred at 25°C under H2atmosphere for 48 hours. LCMS showed the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated to dryness to afford the desired product (1.30 g, 69.4% yield) as yellow oil. Step 3 tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate To a mixture of compound 4 (1.30 g, 3.60 mmol) in 1,4-dioxane (20 mL) were added B2Pin2(1.10 g, 4.30 mmol), KOAc (1.06 g, 10.80 mmol) and Pd(dppf)Cl2(0.40 g, 0.50 mmol), then it was stirred at 95°C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EA / PE=8%) to afford the desired product (1.10 g, 66.6% yield) as colorless oil. Step 4 tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4- methylthiophen-2-yl)-3-fluorophenyl)piperidine-1-carboxylate To a mixture of compound 5 (200 mg, 0.49 mmol) and compound 6 (192 mg, 0.49 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) were added K3PO4(313 mg, 1.48 mmol) and Pd(dppf)Cl2(60 mg, 0.07 mmol), then it was stirred at 95°C under N2atmosphere for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EA / PE=30%) to afford the desired product (150 mg, 46.5% yield) was obtained as light- yellow oil. LCMS (ESI): mass calc’d. for C31H43FN3O5S 588.29, m / z found 588.5 [M+H]+. Step 5 (S)-(3-aminopyrrolidin-1-yl)(5-(2-fluoro-4-(piperidin-4-yl)phenyl)-3-methylthiophen- 2-yl)methanone To a mixture of compound 7 (150 mg, 0.25 mmol) in EtOAc (2 mL) was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at 25°C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford the desired product (Compound 129; 10.8 mg, 25.5% yield) was obtained as a white solid. LCMS (ESI): mass calc’d. for C21H26FN3OS 387.18, m / z found 388.3 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.24 - 7.12 (m, 2H), 4.01 - 3.92 (m, 2H), 3.86 - 3.72 (m, 2H), 3.68 - 3.61 (m, 1H), 3.55 - 3.48 (m, 2H), 3.20 - 3.09 (m, 2H), 3.02 - 2.93 (m, 1H), 2.46 -- 2.34 (m, 4H), 2.15 - 2.03 (m, 3H), 1.98 - 1.85 (m, 2H). EXAMPLE 15: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(2-methyl-4-(1- methylpiperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 134) Step 1 tert-butyl 4-(4-bromo-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 1-bromo-4-iodo-2-methylbenzene (1000 mg, 3.4 mmol) in dioxane / H2O=8:1(18 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydropyridine-1(2H)-carboxylate (1044.8 mg, 3.4 mmol), K2CO3(1396.4 mg, 10.1 mmol) and Pd(dppf)Cl2DCM (549.6 mg, 0.67 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc = 5:1) to give tert-butyl 4-(4-bromo-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (580 mg, 46.3 % yield) as a yellow oil. LCMS (ESI) calc’d for C17H23BrNO2+ [M + H]+ m / z 352.09, found 352. Step 2 tert-butyl 4-(4-bromo-3-methylphenyl)piperidine-1-carboxylate To a solution of 4-(4-bromo-3-methylphenyl)-1-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (580 mg, 1.53 mmol) in EtOAc (10 mL) was added PtO2(34.8 mg, 0.15 mmol). The mixture was stirred at rt under H2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-(4-bromo- 3-methylphenyl)piperidine-1-carboxylate (513 mg, 83.6% yield) as a yellow oil. LCMS (ESI) calc’d for C13H19BrN+ [M + H]+ m / z 268.07, found 268. Step 34-(4-bromo-3-methylphenyl)piperidine To a solution of tert-butyl 4-(4-bromo-3-methylphenyl)piperidine-1-carboxylate (513 mg, 1.44 mmol) in 5 mL EtOAc was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was concentrated under reduced pressure to give 4-(4-bromo-3- methylphenyl)piperidine (533 mg, 72.62% yield) as a yellow oil. LCMS (ESI) calc’d for C12H17BrN+ [M + H]+ m / z 254.06, found 254. Step 44-(4-bromo-3-methylphenyl)-1-methylpiperidine To a solution of 4-(4-bromo-3-methylphenyl)piperidine (533 mg, 2.1 mmol) in DCM (5 mL) was added HCHO (125.8 mg, 4.2 mmol, 37 wt% in H2O) and NaBH(OAc)3(1333.4 mg, 6.3 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 10) to give 4-(4-bromo-3-methylphenyl)-1-methylpiperidine (200 mg, 33.8% yield) as a yellow oil. LCMS (ESI) calc’d for C13H19BrN+ [M + H]+ m / z 268.07, found 268. Step 51-methyl-4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromo-3-methylphenyl)-1-methylpiperidine (200 mg, 0.75 mmol) in dioxane (10 mL) were added B2Pin2(189.4 mg, 0.75 mmol), KOAc (220 mg, 2.2 mmol) and Pd(dppf)Cl2DCM (121.7 mg, 0.15 mmol). The mixture was stirred at 100 ºC for 16 h. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc / petroleum ether = 5:1) to give 1- methyl-4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (250 mg, 101 % yield) as a yellow solid. LCMS (ESI) calc’d for C19H31BNO2+ [M + H]+ m / z 316.25, found 316. Step 6 tert-butyl (S)-(1-(3-methyl-5-(2-methyl-4-(1-methylpiperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (280 mg, 0.72 mmol) in dioxane / H2O=8:1(18 mL) were added 1-methyl-4-(3- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (226.7 mg, 0.72 mmol), K3PO4(458 mg, 2.16 mmol) and Pd(dppf)Cl2DCM (117.4 mg, 0.14 mmol). The mixture was stirred at 95 ºC for 16 h. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc = 1:5) to give tert-butyl (S)-(1-(3-methyl-5-(2-methyl-4-(1- methylpiperidin-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 53 % yield) as a yellow oil. LCMS (ESI) calc’d for C28H40N3O3S+ [M + H]+ m / z 498.28, found 498. Step 7 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(2-methyl-4-(1-methylpiperidin-4- yl)phenyl)thiophen-2-yl)methanone A solution of tert-butyl (S)-(1-(3-methyl-5-(2-methyl-4-(1-methylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 0.39 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give the (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(2-methyl-4-(1-methylpiperidin-4- yl)phenyl)thiophen-2-yl)methanone (Compound 134; 7.1 mg, 4.4 % yield) as a yellow solid. LCMS (ESI) calc’d for C24H34N3OS+ [M + H]+ m / z 412.24, found 412.1H NMR (400 MHz, MeOD) δ 7.25 (d, J = 7.9 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 3.88 (t, J = 7.2 Hz, 2H), 3.81 – 3.70 (m, 1H), 3.69 – 3.57 (m, 2H), 3.52 (d, J = 12.1 Hz, 2H), 3.05 (t, J = 11.8 Hz, 2H), 2.87 – 2.73 (m, 4H), 2.40 – 2.29 (m, 4H), 2.26 (s, 3H), 2.04 (dd, J = 17.5, 13.1 Hz, 3H), 1.89 (dd, J = 24.7, 12.0 Hz, 2H). EXAMPLE 16: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(3-chloro-4-(1- methylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 135) Step 14-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine A solution of tert-butyl 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate (292 mg, 0.69 mmol) in HCl (3 mL, 2M in EtOAc) was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness to afford the desired product (300 mg, 94.5% yield) as a colorless oil. Step 24-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1- methylpiperidine To a mixture of compound 2 (300 mg, 0.93 mmol) in DCM (30 mL) was added STAB (1.78 g, 8.39 mmol), HCHO (303 mg, 3.73 mmol) and Na2SO4(40 mg, 0.28 mmol), then it was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. Then it was diluted with ethyl acetate and filtrated. The filtrate was concentrated to dryness to afford the desired product (360 mg, 97.7% yield) was obtained as yellow oil. Step 3 tert-butyl (S)-(1-(5-(3-chloro-4-(1-methylpiperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 3 (285 mg, 0.85 mmol) and compound 4 (300 mg, 0.77 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) was added K3PO4(540 mg, 2.54 mmol) and Pd(dppf)Cl2(104 mg, 0.13 mmol), then it was stirred at 95 °C for 16 hours under N2atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM = 20%) to afford the desired product (227 mg, 43.9% yield) as a black solid. Step 4 (S)-(3-aminopyrrolidin-1-yl)(5-(3-chloro-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone A solution of compound 5 (227 mg, 0.44 mmol) in HCl (3 mL, 2M in EtOAc) was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford the desired product (Compound 135; 58.5 mg, 30.7% yield) as an off-white solid. MS (ESI): mass calc’d. for C22H29ClN3OS 418.17, m / z found 418.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.65 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 3.82 - 3.72 (m, 2H), 3.68 - 3.54 (m, 2H), 3.32 (s, 1H), 3.10 - 3.00 (m, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.26 - 2.15 (m, 3H), 1.92 - 1.82 (m, 3H), 1.81 - 1.72 (m, 2H).

[0052] EXAMPLE 17: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(3-fluoro-4-(1- methylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 136) Step 1 Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate(1 g, 3.2 mmol) and 4-bromo-2-fluoro-1-iodobenzene (1.44 g, 4.8 mmol) in dioxane / H2O=4:1(10 mL) were added K2CO3(1.33 g, 9.6 mmol) and Pd(dppf)Cl2DCM (0.26 g, 0.36 mmol), the mixture was stirred at 80ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6- dihydropyridine-1(2H)-carboxylate (0.84 g, 71.88% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.26 – 7.21 (m, 2H), 7.13 – 7.09 (m, 1H), 5.94 – 5.92 (m, 1H), 4.06 (9, J = 5.8, 2H), 3.61 (t, J = 5.8 Hz, 2H), 2.49 – 2.44 (m, 2H), 1.49 (s, 9H). Step 2 Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (840 mg, 2.3514 mmol) in 5 mL EtOAc was added PtO2(84.4 mg, 0.3715 mmol), the mixture was stirred under H2 atmosphere at 25 ºC for 48 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (500 mg, 58.6% yield) as a colorless oil. LCMS (ESI): calc’d. for C15H21BrFNO2 + [M - Me + H] m / z 345.0, found 344.9. Step 3 Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (500 mg, 1.3918 mmol) and B2Pin2(424.1 mg, 1.6701 mmol) in dioxane (10 mL) were added Pd(dppf)Cl2DCM (227.3 mg, 0.2783 mmol) and KOAc (409.8 mg, 4.1754 mmol), the mixture was stirred at 95ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert- butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1- carboxylate (438 mg, 75.9% yield) as a white solid. LCMS (ESI): calc’d. for C21H31BFNO4 [M - Me] m / z 391.23, found 391.3. Step 4 Synthesis of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate(438 mg, 1.078 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 hours. After the reaction, the solvent was removed under reduced pressure to afford 4-(2-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)piperidine (400 mg, 97.26% yield) as a yellowish solid. LCMS (ESI) calc’d for C17H26BFNO2 + [M + H] m / z 306.20, found 306.3. Step 5 Synthesis of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1- methylpiperidine To a solution of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine(400 mg, 1.3106 mmol) in DCM were added HCHO (157.43 mg, 5.2424 mmol) and NaBH(OAc)3(833.3 mg, 3.9318 mmol), the mixture was stirred at 25ºC for 2 hours. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure to afford 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1- methylpiperidine (400 mg, 90.83% yield) as a yellowish oil. LCMS (ESI) calc’d for C18H28BFNO2 + [M + H] m / z 320.21, found 320.1. Step 6 Synthesis of tert-butyl (S)-(1-(5-(3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate(150 mg, 0.3853 mmol) and 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-1-methylpiperidine(160 mg, 0.5008 mmol) in EtOH / DME(1:1) were added Na2CO3(122.5 mg, 1.1559 mmol) and Pd(PPh3)4(44.5 mg, 0.0385 mmol), the mixture was stirred at 95ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to afford tert-butyl (S)-(1-(5-(3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (60 mg, 30.42% yield) as a white solid. LCMS (ESI) calc’d for C27H37FN3O3S+ [M + H] m / z 502.25, found 502.3. Step 7 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(3-fluoro-4-(1-methylpiperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(5-(3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (60 mg, 0.1196 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 4 hours. After the reaction, the mixture was filtered and the filter cake was washed with EtOAc for several times to afford (S)-(3-aminopyrrolidin-1-yl)(5-(3-fluoro-4-(1-methylpiperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 136; 13.7 mg, 27.34% yield) as a white solid. LCMS (ESI) calc’d for C22H29FN3OS+ [M + H] m / z 402.20, found 402.2.1H NMR (400 MHz, MeOD) δ 7.47 (d, J = 8.0 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.30 (s, 1H), 4.01 – 3.97 (m, 2H), 3.88 – 3.70 (m, 3H), 3.64 (d, J = 12.1 Hz, 2H), 3.25 – 3.20 (m, 3H), 2.93 (s, 3H), 2.48 – 2.43 (m, 1H), 2.36 (s, 3H), 2.18 – 2.10 (m, 5H). EXAMPLE 18: Synthesis of ((S)-3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-((tetrahydro- 2H-pyran-3-yl)methyl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 139) Step 1 tert-butyl((3S)-1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3-yl)methyl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate (340 mg, 0.724 mmol) in DCM (6 mL) were added oxane-3-carbaldehyde (247.9 mg, 2.172 mmol), NaBH(OAc)3(230.17 mg, 1.086 mmol) and HOAc (87 mg, 1.448 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (300 mg, 65.68% yield) as a yellow oil. Step 2 ((S)-3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3- yl)methyl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone To the solution of tert-butyl((3S)-1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3- yl)methyl)piperidin-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (300 mg, 0.5284 mmol) in DCM (5 mL) was added TFA (903.72 mg, 7.926 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The residue was purified by prep-HPLC to give the desired product (Compound 139; 30 mg, 10.92% yield) as a yellow solid. MS (ESI): mass calc’d for C27H38N3O2S 468, m / z found 468 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 4.01 – 3.91 (m, 3H), 3.86 – 3.66 (m, 6H), 3.54 – 3.47 (m, 1H), 3.19 – 3.03 (m, 4H), 2.94 (t, J = 11.6 Hz, 1H), 2.44 (m, 1H), 2.35 (s, 3H), 2.24 – 1.92 (m, 8H), 1.68 (m, 2H), 1.51 – 1.41 (m, 1H). EXAMPLE 19: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(3-fluoro-4-(piperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 140) Step 1 Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate To a solution of NiCl2·DME (0.07 g, 0.3 mmol) and dtbppy (0.1 g, 0.3 mmol) in 5 mL DMA were added 4-bromo-2-fluoro-1-iodobenzene (0.5 g, 1.7 mmol), 1-(tert-butyl) 4-(1,3- dioxoisoindolin-2-yl) piperidine-1,4-dicarboxylate (0.96 g, 2.5 mmol) and Zn powder (0.22 g, 3.4 mmol), the mixture was stirred at 40 ºC under N2for 16 hours. After the reaction, H2O was added and the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4and filtered, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4- (4-bromo-2-fluorophenyl)piperidine-1-carboxylate (183 mg, 29.41% yield) as a colorless oil. Step 2 Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (183 mg, 0.5094 mmol) and B2Pin2(155.3 mg, 0.6112 mmol) in dioxane (6 mL) were added Pd(dppf)Cl2DCM (41.6 mg, 0.0509 mmol) and KOAc (150 mg, 1.5282 mmol), the mixture was stirred at 100 ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4- (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (150 mg, 71.02% yield) as a white solid. Step 3 Synthesis of tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1- carbonyl)-4-methylthiophen-2-yl)-2-fluorophenyl)piperidine-1-carboxylate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (140 mg, 0.3596 mmol) and tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (146.1 mg, 0.3596 mmol) in dioxane / H2O (9 mL, v:v = 8:1) were added K3PO4(229 mg, 1.0788 mmol) and Pd(dppf)Cl2DCM (58.7 mg, 0.0719 mmol), the mixture was stirred at 95ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl (S)-4-(4-(5-(3-((tert- butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2- fluorophenyl)piperidine-1-carboxylate (90 mg, 41.46% yield) as a white solid. LCMS (ESI): calc’d. for C31H43FN3O5S + [M + H] m / z 588.29, found 588.3. Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(3-fluoro-4-(piperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1- carbonyl)-4-methylthiophen-2-yl)-2-fluorophenyl)piperidine-1-carboxylate (85 mg, 0.1444 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 hours. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford the (S)-(3-aminopyrrolidin-1-yl)(5-(3-fluoro-4- (piperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 140; 13.7 mg, 24.24% yield) as a yellow solid. LCMS (ESI) calc’d for C21H27FN3OS+ [M + H] m / z 388.19, found 388.1.1H NMR (400 MHz, MeOD) δ 7.47 – 7.45 (m, 1H), 7.42 – 7.35 (m, 2H), 7.29 (s, 1H), 3.99 – 3.94 (m, 2H), 3.87 – 3.80 (m, 1H), 3.78 – 3.71 (m, 1H), 3.69 – 3.63 (m, 1H), 3.52 (d, J = 12.8 Hz, 2H), 3.27 – 3.14 (m, 3H), 2.46 – 2.37 (m, 1H), 2.35 (s, 3H), 2.15 – 1.97 (m, 5H). EXAMPLE 20: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(3- methoxypropyl)piperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 141) Step 1 Synthesis of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate To a solution of 4-(4-bromophenyl)piperidine (8 g, 33.3 mmol) and Boc2O (8.72 g, 39.9 mmol) in 100 mL DCM was added TEA, the mixture was stirred at 25 ºC for 12 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10.09 g, 87.99% yield) as a yellowish oil.1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 4.24 (d, J = 13.2 Hz, 1H), 2.79 (t, J = 12.2 Hz, 2H), 2.64 – 2.57 (m, 1H), 1.81 – 1.78 (m, 2H), 1.63 – 1.53 (m, 3H), 1.48 (s, 9H). Step 2 Synthesis of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.3 mmol), B2Pin2(8.93 g, 35.1 mmol) and KOAc (8.63 g, 87.9 mmol) in 100 mL dioxane was added Pd(dppf)Cl2DCM (2.39 g, 2.9 mmol), the mixture was stirred at 95 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (10 g, 87.03% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 4.24 (d, J = 13.4 Hz, 1H), 2.79 (t, J = 12.6, 2H), 2.68 – 2.62 (m, 1H), 1.81 (d, J = 12.6 Hz, 1H), 1.68 – 1.58 (m, 1H), 1.48 (s, 9H), 1.33 (s, 12H). Step 3 Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate(10 g, 25.8 mmol) in 20 mL EtOAc was added HCl (60 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 16 hours. After the reaction, the solvent was removed under reduced pressure to afford 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperidine hydrochloride (8 g, 94.96% yield) as a yellow solid. LCMS (ESI): calc’d. for C17H27BNO2 + [M + H] m / z 288.21, found 288.2. Step 4 Synthesis of tert-butyl (S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (9.62 g, 24.7 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine hydrochloride (8 g, 24.7 mmol) and K3PO4(15.73 g, 74.1 mmol) in dioxane / H2O (90 mL, v:v = 8:1) was added Pd(dppf)Cl2DCM (2.02 g, 2.47 mmol), the mixture was stirred at 95 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl (S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (14 g crude, 92.48% yield) as a brown solid. LCMS (ESI) calc’d for C26H36N3O3S + [M + H] m / z 470.25, found 470.3. Step 5 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(3-methoxypropyl)piperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (300 mg, 0.6388 mmol) and 1-bromo-3-methoxypropane (195.5 mg, 1.2776 mmol) in 5 mL MeCN was added K2CO3, the mixture was stirred at 70 ºC for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl (S)-(1-(5-(4-(1-(3- methoxypropyl)piperidin-4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3- yl)carbamate (160 mg, 43.93% yield) as a yellow solid. LCMS (ESI) calc’d for C30H44N3O4S+ [M + H] m / z 542.31, found 542.3. Step 6 Synthesis of tert-butyl (S)-(1-(5-(4-(1-(3-methoxypropyl)piperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-(4-(1-(3-methoxypropyl)piperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (160 mg, 0.2953 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 hours. After the reaction, the mixture was filtered, the filter cake was washed with EtOAc for several times to afford (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(3-methoxypropyl)piperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 141; 15.2 mg, 10.8% yield) as a yellow solid. LCMS (ESI) calc’d for C25H36N3O2S+ [M + H] m / z 442.25, found 442.2.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H), 4.01 – 3.98 (m, 2H), 3.87 – 3.68 (m, 5H), 3.54 – 3.52 (m, 2H), 3.37 (s, 3H), 3.28 – 3.24 (m, 2H), 3.17 – 3.11 (m, 2H), 2.98 – 2.92 (m, 1H), 2.50 – 2.41 (m, 1H), 2.36 (s, 3H), 2.16 – 2.00 (m, 7H). The following compounds are prepared analogously to the methods described in this example:

[0053] EXAMPLE 21: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(2- methoxyethyl)piperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 142) Step 1 tert-butyl(S)-(1-(5-(4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate (300 mg, 0.6388 mmol) in MeCN (6 mL) were added 1-bromo-2-methoxyethane (177.57 mg, 1.2776 mmol) and K2CO3(264.87 mg, 1.9164 mmol). The mixture was stirred at 70ºC for 16 h. The LCMS showed the reaction was completed and the desired product was found. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH=95 / 5) to give tert-butyl (S)-(1-(5-(4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (110 mg, 29.37% yield) as a yellow solid. Step 2 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (110 mg, 0.2084 mmol) in EtOAc (4 mL) was added HCl (3 ml, 2M in EtOAc).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 142; 20 mg, 20.20% yield) as a yellow solid. MS (ESI): mass calc’d for C24H34N3O2S 428, m / z found 428 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.46 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 3.67 (m, 2H), 3.57 – 3.44 (m, 4H), 3.25 (t, J = 3.6 Hz, 4H), 3.03 (d, J = 11.2 Hz, 2H), 2.55 (t, J = 5.6 Hz, 2H), 2.47 (m, 1H), 2.22 (s, 3H), 2.13 (m, 3H), 1.78 – 1.67 (m, 5H).

[0054] EXAMPLE 22: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(3-methyl-4-(1- methylpiperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 144) Step 1 tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate To a solution of NiCl2-DME (0.15 g, 0.00068 mol) and dtbbpy (0.18 g, 0.00068 mol) in 15 mL DMA were added 4-bromo-1-iodo-2-methylbenzene (1 g, 0.0034 mol), 1-(tert- butyl) 4-(1,3-dioxoisoindolin-2-yl) piperidine-1,4-dicarboxylate (1.91 g, 0.0051 mol) and Zn powder (0.44 g, 0.0068 mol), the mixture was stirred at 40ºC under N2for 16 h. After the reaction, the H2O was added and the mixture was extracted with EtOAc for 3 times. Combined with EA phases, washed with brine, dried over Na2SO4and filtered, the solvent was removed under reduced pressure, the residue was purified by column chromatography to give tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (0.4 g, 29.41% yield)as a yellow oil. Step 24-(4-bromo-2-methylphenyl)piperidine To the solution of tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (400 mg, 1.1258 mmol) in EtOAc (2 mL) was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to give the desired product (280 mg, 88.07% yield) as a yellow solid. Step 34-(4-bromo-2-methylphenyl)-1-methylpiperidine To the solution of 4-(4-bromo-2-methylphenyl)piperidine (280 mg, 1.1016 mmol) in DCM (15 mL) was added 37% HCHO (268.2 mg), Na2SO4(93.9 mg, 0.6609 mmol) and NaBH(OAc)3(1400.8 mg, 6.6095 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found.15 mL NaHCO3was added and the mixture was extracted with EtOAc (3*20 mL). Combined the EtOAc phases, washed with brine, dried over anhydrous Na2SO4and evaporated in vacuum. The residue was purified by silica gel column chromatography to give the desired product (210 mg, 63.97% yield) as a yellow oil. Step 41-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To the solution of 4-(4-bromo-2-methylphenyl)-1-methylpiperidine (210 mg, 0.7830 mmol) in 1,4-dioxane (8 mL) were added B2Pin2(218.7 mg, 0.8613 mmol), Pd(dppf)Cl2DCM (127.8 mg, 0.1566 mmol) and KOAc (230.5 mg, 2.349 mmol), the mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (170 mg, 61.98% yield) as a yellow solid. Step 5 tert-butyl(S)-(1-(3-methyl-5-(3-methyl-4-(1-methylpiperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of 1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine (170 mg, 0.5392 mmol) in dioxane / H2O=8:1 (9 mL) was added tert- butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (209.9 mg, 0.5392 mmol), K3PO4(343.4 mg, 1.6176 mmol) and Pd(dppf)Cl2DCM (88.0 mg, 0.1078 mmol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (190 mg, 63.72% yield) as a yellow solid. Step 6 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(3-methyl-4-(1-methylpiperidin-4- yl)phenyl)thiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(3-methyl-5-(3-methyl-4-(1-methylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (190 mg, 0.3818 mmol) in EtOAc (3 mL) was added HCl (5 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 144; 20 mg, 11.86% yield) as a yellow solid. MS (ESI): mass calc’d for C23H32N3OS 398, m / z found 398 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.45 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 3.83 – 3.75 (m, 2H), 3.65 (m, 2H), 3.37 (d, J = 5.2 Hz, 1H), 3.06 (d, J = 11.6 Hz, 2H), 2.88 – 2.77 (m, 1H), 2.39 (d, J = 6.0 Hz, 6H), 2.34 (s, 3H), 2.29 – 2.18 (m, 3H), 1.83 (m, 5H). EXAMPLE 23: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-((tetrahydro- 2H-pyran-4-yl)methyl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 147) Step 1 tert-butyl(S)-(1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl (S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate (260 mg, 0.5536 mmol) in DCM (6 mL) was added oxane-4-carbaldehyde (442.32 mg, 3.8752 mmol), Sodium triacetoxyborohydride (175.99 mg, 0.8304 mmol) and HOAc (66.49 mg, 1.1072 mmol).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product (180 mg, 51.54% yield) as a yellow solid. Step 2 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4- yl)methyl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4- yl)methyl)piperidin-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (180 mg, 0.3170 mmol) in DCM (5 mL) was added TFA (542.17 mg, 4.755 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 147; 30 mg, 18.20% yield) as a yellow solid. MS (ESI): mass calc’d for C27H37N3O2S 467, m / z found 468 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (s, 1H), 4.06 – 3.92 (m, 4H), 3.89 – 3.75 (m, 2H), 3.73 – 3.58 (m, 3H), 3.49 (t, J = 11.6 Hz, 2H), 3.02 (d, J = 5.6 Hz, 4H), 2.93 (t, J = 11.6 Hz, 1H), 2.49 – 2.34 (m, 4H), 2.22 – 1.99 (m, 6H), 1.76 (d, J = 12.8 Hz, 2H), 1.47 – 1.36 (m, 2H).

[0055] EXAMPLE 24: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-cyclohexylpiperazin-1- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 148) Step 1 tert-butyl(S)-(1-(3-methyl-5-(4-(piperazin-1-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (200 mg, 0.6940 mmol) in dioxane / H2O = 8:1 (9 mL) was added tert- butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidin-3-yl)carbamate (270.18 mg, 0.6940 mmol), K3PO4(441.95 mg, 2.082 mmol) and Pd(dppf)Cl2DCM (113.26 mg, 0.1388 mmol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (130 mg, 35.82% yield) as a yellow solid. Step 2 tert-butyl(S)-(1-(5-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of tert-butyl(S)-(1-(3-methyl-5-(4-(piperazin-1-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (130 mg, 0.2762 mmol) in EtOH (5 mL) was added cyclohexanone (189.75 mg, 1.9334 mmol), NaBH3CN (26.03 mg, 0.4143 mmol) and HOAc (33.17 mg, 0.5524 mmol). The mixture was stirred at 65ºC for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product (90 mg, 53.04% yield) as a yellow solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-3- methylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (90 mg, 0.1628 mmol) in EtOAc (3 mL) was added HCl (4 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to give the desired product (Compound 148; 40 mg, 48.83% yield) as a yellow solid. MS (ESI): mass calc’d for C26H37N4OS 453, m / z found 453 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.48 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.88 (dd, J = 15.6, 10.8 Hz, 4H), 3.82 – 3.64 (m, 2H), 3.59 (dd, J = 15.6, 10.4 Hz, 3H), 3.26 (s, 1H), 3.16 (s, 1H), 3.09 (t, J = 12.4 Hz, 2H), 2.35 (td, J = 13.6, 7.2 Hz, 1H), 2.25 (s, 3H), 2.12 (d, J = 11.2 Hz, 2H), 2.04 (dd, J = 11.6, 6.4 Hz, 1H), 1.89 (t, J = 12.8 Hz, 2H), 1.64 (d, J = 12.8 Hz, 1H), 1.57 – 1.06 (m, 6H).

[0056] EXAMPLE 25: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(3-methyl-4- (piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 149) Step 1 Synthesis of 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) piperidine-1,4-dicarboxylate To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10 g, 43.4 mmol), 2-hydroxyisoindole-1,3-dione (7.08 g, 43.4 mmol) and DMAP (0.27 g, 2.1 mmol) in 60 mL DCM was added DCC in 40 mL DCM, the mixture was stirred at 25ºC for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 1-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) piperidine- 1,4-dicarboxylate (10.7 g, yield = 64.98%) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.90 - 7.87 (m, 2H), 7.82 – 7.79 (m, 2H), 4.04 (d, J = 12.0 Hz, 2H), 3.05 – 2.98 (m, 2H), 2.95 – 2.88 (m, 1H), 2.19 – 2.05 (m, 2H), 1.89 – 1.81 (m, 2H), 1.47 (s, 9H). Step 2 Synthesis of tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate To a solution of NiCl2.DME (0.15 g, 0.6 mmol) and dtbbpy (0.2 g, 0.7 mmol) in 10 mL DMA were added 4-bromo-1-iodo-2-methylbenzene (1 g, 3.4 mmol), 1-(tert-butyl) 4- (1,3-dioxoisoindolin-2-yl) piperidine-1,4-dicarboxylate (1.91 g, 5.1 mmol) and Zn powder (0.44 g, 6.8 mmol), the mixture was stirred at 40 ºC under N2for 16 hours. After the reaction, the H2O was added and the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4and filtered, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert- butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (0.73 g, yield = 58.82%) as a colorless oil. LCMS (ESI) calc’d for C16H22BrNO2+ [M – Me + H] m / z 339.08, found 339.0. Step 3 Synthesis of tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate(730 mg, 2.0547 mmol), B2Pin2(626.2 mg, 2.4656 mmol) and KOAc(605 mg, 6.1641 mmol) in 10 mL dioxane was added Pd(dppf)Cl2DCM (335.6 mg, 0.4109 mmol), the mixture was stirred at 100 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 4-(2- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (446 mg, 53% yield) as a white solid. LCMS (ESI): calc’d. for C19H29BNO4+ [M –tBu + 2H] m / z 346.22, found 346.1. Step 4 Synthesis of tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1- carbonyl)-4-methylthiophen-2-yl)-2-methylphenyl)piperidine-1-carboxylate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (120 mg, 0.3082 mmol), tert-butyl4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (148.8 mg, 0.3698 mmol) and K3PO4(196.3 mg, 0.9245 mmol) in dioxane / H2O(9 mL, v:v = 8:1) was added Pd(dppf)Cl2DCM (50.3 mg, 0.0616 mmol), the mixture was stirred at 95 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl (S)-4-(4-(5-(3-((tert- butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2- methylphenyl)piperidine-1-carboxylate (82 mg, 45.04% yield) as a yellow solid. LCMS (ESI) calc’d for C32H46N3O5S+ [M + H] m / z 584.32, found 584.3. Step 5 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(3-methyl-4-(piperidin-4- yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1- carbonyl)-4-methylthiophen-2-yl)-2-methylphenyl)piperidine-1-carboxylate (82 mg, 0.1402 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 hours. After the reaction, the mixture was filtered and the filter cake was washed with EtOAc for several times to afford (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(3-methyl-4- (piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 149; 20.2 mg, 34.95% yield) as a yellow solid. LCMS (ESI) calc’d for C22H30N3OS+ [M + H] m / z 384.21, found 384.1.1H NMR (400 MHz, MeOD) δ 7.49 – 7.46 (m, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (s, 2H), 4.02 (s, 2H), 3.85 – 3.71 (m, 3H), 3.52 (d, J = 10.5 Hz, 2H), 3.20 (s, 3H), 2.50 - 2.42 (m, 4H), 2.35 (s, 3H), 2.20 – 2.12 (m, 1H), 2.01 – 1.94 (m, 4H). EXAMPLE 26: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(4-(tetrahydro- 2H-pyran-4-yl)piperazin-1-yl)phenyl)thiophen-2-yl)methanone (Compound 151) Step 11-(tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine To the solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (700 mg, 2.4289 mmol) in EtOH (10 mL) was added oxan-4-one (1702.2 mg, 17.002 mmol), NaBH3CN (228.9 mg, 3.6433 mmol) and HOAc (291.7 mg, 4.8578 mmol). The mixture was stirred at 65ºC for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH=95 / 5) to give 1- (tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (500 mg, 49.76% yield) as a yellow solid. Step 2 tert-butyl(S)-(1-(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of 1-(tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperazine (300 mg, 0.8058 mmol) in dioxane / H2O=8:1 (9 mL) was added tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidin-3- yl)carbamate (313.7 mg, 0.8058 mmol), K3PO4(513.1 mg, 2.4173 mmol) and Pd(dppf)Cl2DCM (131.5 mg, 0.1611 mmol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (180 mg, 36.24% yield) as a yellow solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1- yl)phenyl)thiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (180 mg, 0.3245 mmol) in DCM (5 mL) was added TFA (555 mg, 4.8675 mmol).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 151; 50 mg, 32.20% yield) as a yellow solid. MS (ESI): mass calc’d for C25H35N4O2S 455, m / z found 455 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.03 (dd, J = 11.2, 3.6 Hz, 2H), 3.79 (dt, J = 13.6, 6.8 Hz, 2H), 3.72 – 3.55 (m, 2H), 3.45 (t, J = 11.6 Hz, 2H), 3.37 (d, J = 5.6 Hz, 1H), 3.31 – 3.24 (m, 4H), 2.88 – 2.71 (m, 4H), 2.51 (t, J = 11.6 Hz, 1H), 2.33 (s, 3H),2.18 (s, 1H), 1.92 (d, J = 11.6 Hz, 2H), 1.83 (td, J = 13.2, 6.8 Hz, 1H), 1.68 – 1.47 (m, 2H). EXAMPLE 27: Synthesis of ((S)-3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(4- (tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)thiophen-2-yl)methanone (Compound 152) Step 11-(tetrahydrofuran-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine To the solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (700 mg, 2.4289 mmol) in EtOH (10 mL) was added oxolan-3-one (1463.7 mg, 17.002 mmol), NaBH3CN (228.9 mg, 3.6433 mmol) and HOAc (291.7 mg, 4.8578 mmol).The mixture was stirred at 65ºC for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH=95 / 5) to give 1- (tetrahydrofuran-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (500 mg, 51.71% yield) as a yellow solid. Step 2 tert-butyl((3S)-1-(3-methyl-5-(4-(4-(tetrahydrofuran-3-yl)piperazin-1- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of 1-(tetrahydrofuran-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperazine (250 mg, 0.6978 mmol) in dioxane / H2O=8:1 (9 mL) was added tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidin-3- yl)carbamate (271.7 mg, 0.6978 mmol), K3PO4(444.4 mg, 2.0934 mmol) and Pd(dppf)Cl2DCM (113.9 mg, 0.1395 mmol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (180 mg, 42.93% yield) as a yellow solid. Step 3 ((S)-3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(4-(tetrahydrofuran-3-yl)piperazin-1- yl)phenyl)thiophen-2-yl)methanone To the solution of tert-butyl((3S)-1-(3-methyl-5-(4-(4-(tetrahydrofuran-3- yl)piperazin-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (180 mg, 0.3329 mmol) in DCM (5 mL) was added TFA (569.4 mg, 4.9935 mmol). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (Compound 152; 40 mg, 24.54% yield) as a yellow solid. MS (ESI): mass calc’d for C24H33N4O2S 441, m / z found 441 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.03 – 3.89 (m, 2H), 3.86 – 3.75 (m, 3H), 3.73 – 3.55 (m, 3H), 3.37 (d, J = 5.2 Hz, 1H), 3.28 (t, J = 5.2 Hz, 4H), 3.13 – 3.00 (m, 1H), 2.75 (dt, J = 10.4, 4.8 Hz, 2H), 2.71 – 2.59 (m, 2H), 2.33 (s, 3H), 2.16 (dd, J = 12.0, 4.4 Hz, 2H), 1.92 (dd, J = 12.4, 7.6 Hz, 1H), 1.88 – 1.77 (m, 1H).

[0057] EXAMPLE 28: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-cyclopentylpiperazin- 1-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 153) Step 1 Synthesis of 1-cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (288 mg, 1 mmol) in EtOH (10 mL) were added cyclopentanone (84 mg, 1 mmol), NaBH3CN (94.2 mg, 1.5 mmol) and AcOH (60 mg, 1 mmol). The mixture was stirred at 65ºC for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the resulted mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc = 3 / 7) to give 1-cyclopentyl-4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (208 mg, 55.5% yield) as a white solid. LCMS (ESI) calc’d for C21H34BN2O2+ [M + H]+ m / z 357.27, found 357. Step 2 Synthesis of tert-butyl (S)-(1-(5-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (227 mg, 0.58 mmol) in dioxane / H2O = 8:1 (18 mL) were added 1- cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (207.8 mg, 0.58 mmol), K3PO4(371.3 mg, 1.75 mmol) and Pd(dppf)Cl2DCM (95.2 mg, 0.12 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate 100%) to give tert-butyl (S)-(1-(5-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 45.4 % yield) as a white solid. LCMS (ESI) calc’d for C30H43N4O3S+ [M + H]+ m / z 539.31, found 539. Step 3 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-3- methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(5-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 0.28 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3- aminopyrrolidin-1-yl)(5-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-3-methylthiophen-2- yl)methanone (Compound 153; 53.3 mg, 39.3 % yield) as a yellow solid. LCMS (ESI) calc’d for C26H37N3OS+ [M + H] + m / z 439.27, found 438.1H NMR (400 MHz, MeOD) δ 7.60 (d, J = 5.1 Hz, 2H), 7.17 (s, 1H), 7.11 (d, J = 5.4 Hz, 2H), 4.03 (s, 2H), 3.95 (d, J = 9.0 Hz, 2H), 3.86 (s, 1H), 3.74 (s, 4H), 3.65 (s, 1H), 3.28 (s, 4H), 2.46 (s, 1H), 2.36 (s, 3H), 2.24 (s, 4H), 1.89 (s, 4H), 1.73 (s, 2H).

[0058] EXAMPLE 29: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-ethylpiperazin-1- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 155) Step 11-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (400 mg, 1.39 mmol) and acetaldehyde (306 mg, 6.94 mmol) in EtOH (15 mL) was added AcOH (167 mg, 2.78 mmol) and sodium cyanoborohydride (262 mg, 4.16 mmol), then it was stirred at 65 °C for 6 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM = 4%~5%) to give the desired product (380 mg, 77.9% yield) as light-yellow oil. Step 2 tert-butyl (S)-(1-(5-(4-(4-ethylpiperazin-1-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 2 (270 mg, 0.85 mmol) and compound 3 (332 mg, 0.85 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) was added K3PO4(544 mg, 2.56 mmol) and Pd(dppf)Cl2(139 mg, 0.17 mmol), then it was stirred at 95 °C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EtOAc / PE=0%~100%) to afford compound 4 (300 mg, 63.4% yield) as a brown solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-ethylpiperazin-1-yl)phenyl)-3-methylthiophen-2- yl)methanone A mixture of compound 4 (300 mg, 0.60 mmol) in HCl / EtOAc (3 mL) was stirred at 25 °C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford desired product (Compound 155; 117.6 mg, 48.1% yield) as a white solid. LCMS (ESI): mass calc’d. for C22H31N4OS 399.22, m / z found 399.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.50 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.82 - 3.70 (m, 2H), 3.68 - 3.51 (m, 2H), 3.36 - 3.31 (m, 1H), 3.28 - 3.24 (m, 4H), 2.70 - 2.60 (m, 4H), 2.54 - 2.45 (m, 2H), 2.31 (s, 3H), 2.15 (s, 1H), 1.87 - 1.72 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H). EXAMPLE 30: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)piperidin-4-yl)phenyl)-3-methylthiophen-2- yl)methanone (Compound 156) Step 1 tert-butyl(S)-(1-(3-methyl-5-(4-(piperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine (600 mg, 2.0891 mmol) in dioxane / H2O=8:1 (18 mL) were added tert- butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidin-3-yl)carbamate (813.30 mg, 2.0891 mmol), K3PO4(1330.36 mg, 6.2673 mmol) and Pd(dppf)Cl2DCM (340.94 mg, 0.4178 mmol). The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired product was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA: MeOH=2:1) to give the desired product (700 mg, 67.78% yield) as a yellow solid. Step 2 tert-butyl(S)-(1-(5-(4-(1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)piperidin-4- yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of tetrahydro-4H-thiopyran-4-one 1,1-dioxide (63.11 mg, 0.4259 mmol) in DCE (8 mL) were addedtert-butyl(S)-(1-(3-methyl-5-(4-(piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 0.4259 mmol), NaBH(OAc)3(126.37 mg, 0.5962 mmol) and HOAc (25.6 mg, 0.4259 mmol). The mixture was stirred at 40ºC for 16 h. The LCMS showed the reaction was completed and the desired product was found. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the desired product (50 mg, 17.55% yield) as a yellow solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)piperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(1-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)piperidin-4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (50 mg, 0.0831 mmol) in EtOAc (4 mL) was added HCl(2 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was filtered and concentrated under reduced pressure to give the desired product (Compound 156; 23 mg, 49.70% yield) as a solid. MS (ESI): mass calc’d for C26H36N3O3S2502, m / z found 502 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 3.89 (t, J = 7.6 Hz, 2H), 3.80 – 3.64 (m, 2H), 3.65 – 3.49 (m, 4H), 3.31 – 3.21 (m, 4H), 3.15 (d, J = 12.8 Hz, 2H), 2.86 (d, J = 7.6 Hz, 1H), 2.49 (d, J = 12.4 Hz, 2H), 2.41 – 2.21 (m, 6H), 2.08 (d, J = 6.4 Hz, 5H). EXAMPLE 31: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-cyclobutylpiperazin-1- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 158) Step 11-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To the solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (700 mg, 2.4289 mmol) in EtOH (10 mL) were added cyclobutanone (1191.69 mg, 17.002 mmol), NaBH3CN (228.95 mg, 3.6433 mmol) and HOAc (291.71 mg, 4.8578 mmol). The mixture was stirred at 65ºC for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH=95 / 5) to give 1- cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (650 mg, 70.37% yield) as a yellow solid. Step 2 tert-butyl(S)-(1-(5-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To the solution of 1-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (300 mg, 0.8765 mmol) in dioxane / H2O=8:1 (9 mL) was added tert- butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidin-3-yl)carbamate (341.23 mg, 0.8765 mmol), K3PO4(558.16 mg, 2.6295 mmol) and Pd(dppf)Cl2DCM (143.04 mg, 0.1753 mmol). The mixture was stirred under N2at 95 ºC for 16 h. The LCMS showed the reaction was completed and the desired MS was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (150 mg, 29.36% yield) as a yellow solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-3- methylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (100 mg, 0.1906 mmol) in EtOAc (2 mL) was added HCl (3 mL, 2M in EtOAc).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to give the desired product (Compound 158; 20 mg, 22.25% yield) as a yellow solid. MS (ESI): mass calc’d for C24H33N4OS 425, m / z found 425 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.48 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.87 (dd, J = 23.6, 10.4 Hz, 4H), 3.73 (dt, J = 29.4, 7.6 Hz, 3H), 3.60 (dd, J = 15.2, 6.8 Hz, 1H), 3.48 (d, J = 10.8 Hz, 2H), 3.11 – 2.92 (m, 4H), 2.45 – 2.18 (m, 8H), 2.03 (d, J = 5.2 Hz, 1H), 1.81 (dt, J = 19.6, 9.2 Hz, 2H).

[0059] EXAMPLE 32: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-isopropylpiperazin-1- yl)phenyl)-3-methylthiophen-2-yl)methanone Compound 159) Step 11-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (400 mg, 1.39 mmol) in DCM (40 mL) were added STAB (2.06 g, 9.72 mmol), acetone (322 mg, 5.56 mmol) and Na2SO4(118 mg, 0.83 mmol), then it was stirred at 25 °C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. EtOAc (20 mL * 3) was added and the mixture was concentrated to dryness. The mixture was diluted with sat. NaHCO3solution (50 mL) and then extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4and concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH / DCM=7%) to give the desired product (200 mg, 39.3% yield) as a yellow solid. Step 2 tert-butyl (S)-(1-(5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 2 (200 mg, 0.61 mmol) and compound 3 (189 mg, 0.48 mmol) in 1,4-dioxane (6 mL) and H2O (1 mL) were added K3PO4(386 mg, 1.82 mmol) and Pd(dppf)Cl2(99 mg, 0.12 mmol), then it was stirred at 95 °C under N2for 16 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EtOAc / PE=92%) to afford desired product (124 mg, 36.0% yield) as a yellow solid. Step 3 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-isopropylpiperazin-1-yl)phenyl)-3- methylthiophen-2-yl)methanone A mixture of compound 4 (124 mg, 0.24 mmol) in HCl / EtOAc (2 mL) was stirred at 25 °C for 3 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to afford desired product (Compound 159; 14.5 mg, 14.2% yield) as a white solid. MS (ESI): mass calc’d. for C23H32N4OS 412.23, m / z found 413.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.52 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.83 - 3.73 (m, 2H), 3.69 - 3.51 (m, 2H), 3.38 - 3.33 (m, 1H), 3.30 - 3.24 (m, 4H), 2.79 - 2.69 (m, 5H), 2.33 (s, 3H), 2.24 - 2.12 (m, 1H), 1.91 - 1.73 (m, 1H), 1.14 (d, J = 6.4 Hz, 6H).

[0060] EXAMPLE 33: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(piperazin-1- yl)phenyl)thiophen-2-yl)methanone (Compound 162) Step 1 Synthesis of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate To a solution of 1-(4-bromophenyl)piperazine (5 g, 20.7 mmol) in 60 mL DCM were added Boc2O (5.42 g, 24.8 mmol) and TEA (3.52 g, 34.7 mmol), the mixture was stirred at 25ºC for 2 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford the tert-butyl 4-(4- bromophenyl)piperazine-1-carboxylate (7.043 g, yield = 98.55%) as an off-white solid. MS (ESI): mass calc’d. for C15H22BrN2O2341.09, found 341.0 [M+H]+Step 2 Synthesis of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (7 g, 20.5 mmol) and B2Pin2(6.25 g, 24.6 mmol) in 50 mL 1,4-dioxane were added Pd(dppf)Cl2DCM (3.35 g, 4.1 mmol) and KOAc (6.04 g, 61.5 mmol), the mixture was stirred at 100 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperazin-1-yl pivalate (8 g, 98.05% yield) as a yellow solid. MS (ESI): mass calc’d. for C21H34BN2O4389.26, found 389.2 [M+H]+Step 3 Synthesis of tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1- carbonyl)-4-methylthiophen-2-yl)phenyl)piperazine-1-carboxylate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (200 mg, 0.5137 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (171.0 mg, 0.6164 mmol) in 9 mL dioxane / H2O (v:v = 8:1) were added Pd(dppf)Cl2DCM (83.9 mg, 0.1027 mmol) and K3PO4(327.1 mg, 1.5411 mmol), the mixture was stirred at 95ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl (S)-4-(4-(5-(3-((tert- butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)phenyl)piperazine-1- carboxylate (150 mg, 50.55% yield) as a yellow solid. MS (ESI): mass calc’d. for C30H43N4O5S 571.30, found 571.3 [M+H]+Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(piperazin-1- yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl (S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1- carbonyl)-4-methylthiophen-2-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.2624 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 hours. After the reaction, the mixture was filtered, the filter cake was washed with EtOAc for several times to afford (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(piperazin-1- yl)phenyl)thiophen-2-yl)methanone (Compound 162; 64.5 mg, 63.03% yield) as a yellow solid. MS (ESI): mass calc’d. for C20H27N4OS 371.19, found 371.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.2 Hz, 2H), 7.22 – 7.19 (m, 3H), 4.02 - 4.00 (m, 2H), 3.89 – 3.83 (m, 1H), 3.80 – 3.72 (m, 2H), 3.62 – 3.59 (m, 4H), 3.49 – 3.46 (m, 4H), 2.51 – 2.45 (m, 1H), 2.35 (s, 3H), 2.19 – 2.16 (m, 1H). EXAMPLE 35: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(isochroman-6-yl)-3- methylthiophen-2-yl)methanone (Compound 165) Step 12-(isochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 6-bromo-3,4-dihydro-1H-2-benzopyran (250 mg, 1.17 mmol) in dioxane (10 mL) were added B2Pin2(298 mg, 1.17 mmol), KOAc (345.4 mg, 3.52 mmol) and Pd(dppf)Cl2DCM (191.5 mg, 0.23 mmol). The mixture was stirred at 100 ºC for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using EtOAc: PE=1:8 as eluent to give 2-(isochroman- 6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 62.25 % yield) as a yellow oil. LCMS (ESI) calc’d for C15H22BO3+ [M + H] + m / z 261.17, found 261. Step 2 tert-butyl (S)-(1-(5-(isochroman-6-yl)-3-methylthiophene-2-carbonyl)pyrrolidin-3- yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (300 mg, 0.77 mmol) in dioxane / H2O=8:1 (18 mL) were added 2- (isochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.77 mmol), K3PO4(490.7 mg, 2.31 mmol) and Pd(dppf)Cl2DCM (125.8 mg, 0.15 mmol). The mixture was stirred at 95 ºC for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (S)-(1-(5-(isochroman-6-yl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 55.7 % yield) as a yellow oil. LCMS (ESI) calc’d for C24H31N2O4S+ [M + H]+ m / z 443.20, found 443. Step 4 (S)-(3-aminopyrrolidin-1-yl)(5-(isochroman-6-yl)-3-methylthiophen-2-yl)methanone To the solution of tert-butyl (S)-(1-(5-(isochroman-6-yl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 0.45 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3-aminopyrrolidin-1- yl)(5-(isochroman-6-yl)-3-methylthiophen-2-yl)methanone (Compound 165; 88.6 mg, 54.4 % Yield) as a yellow solid. LCMS (ESI) calc’d for C19H23N2O2S+ [M + H] + m / z 343.15, found 343.1H NMR (400 MHz, MeOD) δ 7.46 – 7.39 (m, 2H), 7.23 (s, 1H), 7.04 (t, J = 8.4 Hz, 1H), 4.75 (s, 2H), 4.00 (d, J = 8.3 Hz, 2H), 3.99 (s, 2H), 3.88 – 3.76 (m, 2H), 3.75 – 3.62 (m, 2H), 2.87 (t, J = 5.7 Hz, 2H), 2.52 – 2.40 (m, 1H), 2.36 (s, 3H), 2.21 – 2.09 (m, 1H).

[0061] EXAMPLE 36: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4- (dimethylamino)tetrahydro-2H-pyran-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 166) Step 14-(4-bromophenyl) tetrahydro-2H-pyran-4-carbonitrile The NaH (2.04 g, 60% in oil) was added in portions to a solution of 2-(4- bromophenyl) acetonitrile (4 g, 0.0204 mol) in dry DMF (40 mL) and stirred at 0 ºC for 1 h. Then 1-bromo-2-(2-bromoethoxy) ethane (4.73 g, 0.0204 mol) was added to the above solution at 0 ºC and stirred at room temperature for overnight. The LCMS showed the reaction was completed and the desired MS was found. After completion of the reaction, the mixture was quenched by addition of water, then extracted with ethyl acetate. The combined organic layer was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4and evaporated in vacuum. The residue was purified by flash chromatography (PE / EA=90 / 10) to give 4-(4-bromophenyl) oxane-4-carbonitrile (4.4 g, 73.04% yield) as a yellow solid. Step 24-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid A solution of 9 M H2SO4was added into 4-(4-bromophenyl) oxane-4-carbonitrile (4 g, 1 eq) and was refluxed at 100 ºC for overnight. After completion of the reaction, the mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4and evaporated in vacuum. Purification of the crude product by silica gel column chromatography to give the desired product (4 g, 84.00% yield) as a yellow solid. Step 34-(4-bromophenyl) tetrahydro-2H-pyran-4-amine 4-(4-bromophenyl) oxane-4-carboxylic acid (4 g, 1 eq) was added into a three-neck round-bottom flask under N2, Toluene (56 mL) and TEA (3.43 g, 2.2 eq) were then added via a syringe. DPPA (4.66 g, 1.1 eq) was added via a syringe and the mixture was stirred at 90 ºC under N2for 2 h. After completion of the reaction, the mixture was cooled to the room temperature and diluted with EtOAc. The combined organic layer was washed with NaHCO3solution and brine, dried over anhydrous Na2SO4and evaporated in vacuum. Then 5 M HCl solution (11 mL) was added and the mixture was refluxed at 100 ºC for 5 h. After the mixture was cooled to the room temperature, toluene was added and evaporated in vacuum. The obtained solid was dissolved into the saturated NaHCO3solution (300 mL) and EtOAc (300 mL). The organic layer was separated, which was washed with brine, dried over anhydrous Na2SO4and evaporated in vacuum. Purification of the crude product by silica gel column chromatography to give the desired product (2.5 g, 57.14% yield) as a yellow solid. Step 44-(4-bromophenyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine To the solution of 4-(4-bromophenyl)oxan-4-amine (1 g, 0.0039 mol) in DCM (50 mL) was added 37% HCHO (0.95 g, 0.0117 mol), Na2SO4(0.33 g, 0.0023 mol) and Sodium triacetoxyborohydride (4.96 g, 0.0234 mol).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found.50 mL NaHCO3solution was added to the reaction mixture, which was extracted with EtOAc (3*50 mL). Combined with organic layers, washed with brine, dried over anhydrous Na2SO4and evaporated in vacuum. Purification of the crude product by silica gel column chromatography to give the desired product (1.1 g, 89.74% yield) as a yellow solid. Step 5 N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro- 2H-pyran-4-amine To the solution of 4-(4-bromophenyl)-N,N-dimethyloxan-4-amine (400 mg, 1.4075 mmol) in 1,4-dioxane (8 mL) were added B2Pin2(393.16 mg, 1.5482 mmol), Pd(dppf)Cl2DCM (229.7 mg, 0.2815 mmol) and KOAc (414.4 mg, 4.2225 mmol).The mixture was stirred at 95 ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired product was found. After cooled to rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product (300 mg, 57.91% yield) as a yellow solid. Step 6 tert-butyl(S)-(1-(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To the solution of N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)tetrahydro-2H-pyran-4-amine (300 mg, 0.9056 mmol) in dioxane / H2O=8:1 (9 mL) were added tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidin-3- yl)carbamate (352.56 mg, 0.9056 mmol), K3PO4(576.70 mg, 2.7168 mmol) and Pd(dppf)Cl2DCM (147.79 mg, 0.1811 mmol). The mixture was stirred at 95ºC under N2for 16 h. The LCMS showed the reaction was completed and the desired product was found. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc: MeOH=10:1) to give the desired product (120 mg, 23.21% yield) as a yellow solid. Step 7 (S)-(3-aminopyrrolidin-1-yl)(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4- yl)phenyl)-3-methylthiophen-2-yl)methanone To the solution of tert-butyl(S)-(1-(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4- yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (120 mg, 0.2336 mmol) in EtOAc (4 mL) was added 2M HCl in EA (5 mL).The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to give the desired product (Compound 166; 60 mg, 58.99% yield) as a yellow solid. MS (ESI): mass calc’d for C23H32N3O2S 414, m / z found 414 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.89 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.43 (s, 1H), 4.01 (d, J = 8.8 Hz, 4H), 3.91 – 3.68 (m, 3H), 3.25 (t, J = 11.6 Hz, 2H), 2.98 (d, J = 12.8 Hz, 2H), 2.67 (s, 6H), 2.52 – 2.42 (m, 1H), 2.38 (s, 3H), 2.19 (t, J = 10.8 Hz, 3H). EXAMPLE 34: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(oxetan-3- yl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 164) Step 14-(4-bromophenyl)-1-(oxetan-3-yl)piperidine To a solution of 4-(4-bromophenyl)piperidine(240 mg, 1 mmol) in DCM(10 mL) was added oxetan-3-one(72 mg, 1 mmol), NaBH(OAc)3(317.7 mg, 1.5 mmol) and HOAc (60 mg, 1 mmol). The mixture was stirred at rt for 3 h. The LCMS showed the reaction was completed and the desired product was found. The resulting mixture was washed with H2O (20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(4-bromophenyl)-1-cyclobutylpiperidine (290 mg, 93.07% yield) as a yellow solid. Step 21-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-(oxetan-3-yl)piperidine (290 mg, 0.98 mmol) in dioxane(10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3,2-dioxaborolane (248 mg, 0.98 mmol), Potassium acetate(288 mg, 3 mmol) and PdCl2(dppf)(160 mg, 0.19 mmol). The mixture was stirred at 95 ºC for 16h. After cooling rt, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using EtOAc as eluent to give 1-(oxetan-3-yl)-4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (258 mg, 73 % yield) as a yellow oil. Step 3 tert-butyl (S)-(1-(3-methyl-5-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)thiophene-2- carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (280 mg, 0.72 mmol) in dioxane / H2O=8:1 (18 mL) were added 1-(oxetan-3- yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (247 mg, 0.72 mmol), K3PO4(458 mg, 2.15 mmol) and Pd(dppf)Cl2DCM (117.4 mg, 0.14 mmol). The mixture was stirred at 95 ºC for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 8) to give tert-butyl (S)-(1-(3-methyl-5-(4-(1-(oxetan-3- yl)piperidin-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (190 mg, 47.7 % yield) as a yellow oil. LCMS (ESI) calc’d for C29H40N3O4S+ [M + H] + m / z 526.28, found 526. Step 4 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(oxetan-3-yl)piperidin-4- yl)phenyl)thiophen-2-yl)methanone To the solution of tert-butyl (S)-(1-(3-methyl-5-(4-(1-(oxetan-3-yl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (190 mg, 0.36 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)thiophen- 2-yl)methanone (Compound 164; 20 mg, 11 % yield) as a white solid. LCMS (ESI) calc’d for C24H31N3O2S+ [M + H] + m / z 426.22, found 426.1H NMR (400 MHz, MeOD) δ 7.63 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H), 4.87 (dd, J = 11.9, 6.0 Hz, 3H), 4.43 (s, 1H), 4.02 – 3.94 (m, 2H),3.81 (tdd, J = 11.8, 8.9, 5.1 Hz, 2H), 3.69 (dd, J = 15.0, 6.7 Hz, 1H), 3.61 (d, J = 9.6 Hz, 2H), 3.11 – 2.89 (m, 3H), 2.44 (td, J = 13.9, 7.6 Hz, 1H), 2.37 (d, J = 8.5 Hz, 3H), 2.14 (td, J = 13.2, 6.1 Hz, 3H), 2.07 – 1.97 (m, 2H). EXAMPLE 37: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(tetrahydro- 2H-thiopyran-4-yl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 167) Step 14-(4-bromophenyl)-1-(tetrahydro-2H-thiopyran-4-yl)piperidine To a solution of 4-(4-bromophenyl)piperidine (1.0 g, 4.2 mmol) and thian-4-one (0.73 g, 6.3 mmol) in EtOH (6 mL) was added NaBH3CN (0.32 g, 5 mmol), followed by HOAc (0.5 g, 8.4 mmol), the mixture was stirred at 25ºC for 12 h. After the reaction, NaOH (30 mL, 1N in H2O) was added and stirred for 30 min, the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4and filtered, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 4-(4-bromophenyl)-1-(thian-4-yl)piperidine (1.5 g crude, 95% yield) as yellowish solid. Step 21-(tetrahydro-2H-thiopyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a mixture of compound 3 (300 mg, 0.88 mmol) in 1,4-dioxane (7 mL) were added B2Pin2(246 mg, 0.97 mmol), KOAc (260 mg, 2.64 mmol) and Pd(dppf)Cl2DCM (719 mg, 0.88 mmol), then it was stirred at 100°C under N2for 12 hours. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc = 2 / 1) to afford desired product (180 mg, 47.4% yield) as a black solid. Step 3 tert-butyl (S)-(1-(3-methyl-5-(4-(1-(tetrahydro-2H-thiopyran-4-yl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a mixture of compound 4 (179 mg, 0.46 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) were added compound 5 (150 mg, 0.39 mmol), K3PO4(245 mg, 1.16 mmol) and Pd(dppf)Cl2DCM (314 mg, 0.39 mmol), then the mixture was stirred at 95°C under N2for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (EtOAc / PE = 1 / 1) to afford desired product (150 mg, 61.5% yield) as a black solid. Step 4 (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(tetrahydro-2H-thiopyran-4- yl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone A mixture of compound 6 (150 mg, 0.26 mmol) in HCl / EtOAc (3 mL) was stirred at 25°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness. The crude product was purified by prep-HPLC to give the desired product (Compound 167; 21.7 mg, 16.9% yield) as a white solid. LCMS (ESI): mass calc’d. for C26H36N3OS2470.23, m / z found 470.3 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.52 (s, 1.5 H), 7.61 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 4.02 - 3.89 (m, 2H), 3.88 - 3.71 (m, 2H), 3.69 - 3.61 (m, 1H), 3.51 (d, J = 12.0 Hz, 2H), 3.27 - 3.15 (m, 3H), 2.92 - 2.74 (m, 5H), 2.48 - 2.38 (m, 3H), 2.35 (s, 3H), 2.16 - 2.02 (m, 5H), 1.97 - 1.85 (m, 2H). EXAMPLE 38: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-ethylpiperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 176) Step 1 Synthesis of 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-ethylpiperidine (220 mg, 0.82 mmol) in dioxane (10 mL) were added B2Pin2(208.3 mg, 0.82 mmol), KOAc (241.5 mg, 2.46 mmol) and Pd(dppf)Cl2DCM (133.9 mg, 0.16 mmol). The mixture was stirred at 100 ºC for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography EA: MeOH=9:1 to give 1-ethyl-4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (180 mg, 66.1 % yield) as a yellow solid. Step 2 Synthesis of tert-butyl (S)-(1-(5-(4-(1-ethylpiperidin-4-yl)phenyl)-3-methylthiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (220 mg, 0.56 mmol) in dioxane / H2O=8:1 (18 mL) were added 1-ethyl-4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (178 mg, 0.56 mmol), K3PO4(360 mg, 1.7 mmol) and Pd(dppf)Cl2DCM (92.2 mg, 0.11 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH / ethyl acetate = 1 / 9) to give tert-butyl (S)-(1-(5-(4-(1-ethylpiperidin-4-yl)phenyl)-3-methylthiophene-2- carbonyl)pyrrolidin-3-yl)carbamate (185 mg, 59.2 % yield) as a yellow solid. LCMS (ESI) calc’d for C28H40N3O3S+ [M + H]+ m / z 498.28, found 498. Step 3 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-ethylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To the solution of tert-butyl (S)-(1-(5-(4-(1-ethylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (185 mg, 0.37 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired MS was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the (S)- (3-aminopyrrolidin-1-yl)(5-(4-(1-ethylpiperidin-4-yl)phenyl)-3-methylthiophen-2- yl)methanone (Compound 176; 7.6 mg, 5 % Yield) as a white solid. LCMS (ESI) calc’d for C23H32N3OS+ [M + H]+ m / z 398.2, found 398.1H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.21 (s, 1H), 3.79 (dt, J = 11.7, 7.0 Hz, 2H), 3.69 – 3.55 (m, 2H), 3.38 – 3.34 (m, 1H), 3.14 (d, J = 11.7 Hz, 2H), 2.62 (tt, J = 11.9, 4.0 Hz, 1H), 2.53 (q, J = 7.3 Hz, 2H), 2.34 (s, 3H), 2.22 – 2.18 (m, 1H), 2.15 (dd, J = 11.8, 2.6 Hz, 2H), 1.89 (t, J = 9.0 Hz, 2H), 1.86 – 1.80 (m, 2H), 1.80 (s, 1H), 1.17 (t, J = 7.2 Hz, 3H).

[0062] EXAMPLE 39: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(tetrahydro- 2H-pyran-4-yl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 178) Step 1 Synthesis of 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-4-yl)piperidine To a solution of 4-(4-bromophenyl)piperidine (500 mg, 2.0821 mmol) and oxan-4-one (208.5 mg, 2.0821 mmol) in DCM (5 mL) were added NaBH3CN (661.9 mg, 3.1231 mmol) and HOAc (125.0 mg, 2.0821 mmol), the mixture was stirred at 25ºC for 12 h. After the reaction, NaOH (15 mL, 1N in H2O) was added and stirred for 30 min, the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4and filtered. The solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 382 mg 4-(4-bromophenyl)-1-(oxan-4- yl)piperidine as yellowish solid. MS (ESI): mass calc’d. for C16H23BrNO 324.10, found 324 [M+1]+ Step 2 Synthesis of 1-(oxan-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-(oxan-4-yl)piperidine (382 mg, 1.1781 mmol) and B2Pin2(359 mg, 1.4137 mmol) in 5 mL 1,4-dioxane were added KOAc (346.9 mg, 3.5343 mmol) and Pd(dppf)Cl2DCM (144.31 mg, 0.1767 mmol), the mixture was stirred at 100ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 443 mg 1-(oxan-4-yl)-4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine as white solid. MS (ESI): mass calc’d. for C22H35BNO3372.27, found 372 [M+1]+Step 3 Synthesis of tert-butyl (S)-(1-(3-methyl-5-(4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (200 mg, 0.5137 mmol) and 1-(oxan-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperidine (228.9 mg, 0.6164 mmol) in dioxane / H2O (9 mL, v / v = 8:1) were added K3PO4(327.1 mg, 1.5411 mmol) and Pd(dppf)Cl2DCM (83.9 mg, 0.1027 mmol), the mixture was stirred at 95ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 150 mg tert-butyl (S)-(1-(3-methyl-5-(4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate as white solid. MS (ESI): mass calc’d. for C31H44N3O4S 554.30, found 554 [M+1]+Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(3-methyl-5-(4-(1-(tetrahydro-2H-pyran-4- yl)piperidin-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (150 mg, 0.2709 mmol) in 2 mL EtOAc was added HCl (4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 h. After the reaction, the mixture was filtered and the filter cake was washed with EtOAc for 3 times to afford 51.6 mg of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1- (tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 178) as yellow solid. MS (ESI): mass calc’d. for C26H36N3O2S 454.25, found 454 [M+1]+.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 4.10 (dd, J = 11.6, 3.9 Hz, 2H), 4.01 – 3.98 (m, 2H), 3.87 – 3.70 (m, 5H), 3.48 (t, J = 11.6 Hz, 3H), 3.20 (t, J = 10.8 Hz, 2H), 2.99 – 2.93 (m, 1H), 2.50 – 2.43 (m, 1H), 2.36 (s, 3H), 2.14 – 2.10 (m, 7H), 1.90 – 1.82 (m, 2H). EXAMPLE 40: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-cyclohexylpiperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 179) Step 1 Synthesis of 4-(4-bromophenyl)-1-cyclopentylpiperidine To a solution of 4-(4-bromophenyl)piperidine (240 mg, 1 mmol) in DCM (10 mL) was added cyclohexanone (98.1 mg, 1 mmol), NaBH(OAc)3(317.7 mg, 1.5 mmol) and HOAc (60 mg, 1 mmol). The mixture was stirred at rt for 3h. The LCMS showed the reaction was completed and the desired product was found. The resulting mixture was washed with H2O (20 mL) and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(4- bromophenyl)-1-cyclohexylpiperidine (244 mg, 72 % yield) as a yellow oil. LCMS (ESI) calc’d for C17H25BrN+ [M + H] + m / z 322.12, found 322. Step 2 Synthesis of 1-cyclohexyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-cyclohexylpiperidine (244 mg, 0.76 mmol) in dioxane (10 mL) were added B2Pin2(192.3 mg, 0.76 mmol), KOAc (222.9 mg, 2.27 mmol) and Pd(dppf)Cl2DCM (123.56 mg, 0.15 mmol). The mixture was stirred at 100 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography EtOAc / MeOH=9:1 as eluent to give 1- cyclohexyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (158 mg, 53.7 % yield) as a yellow oil. LCMS (ESI) calc’d for C23H37BNO2+ [M + H] + m / z 370.29, found 370. Step 3 Synthesis of tert-butyl (S)-(1-(5-(4-(1-cyclohexylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (170 mg, 0.44 mmol) in dioxane / H2O = 8:1 (18 mL) were added 1- cyclohexyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (161.3 mg, 0.44 mmol), K3PO4(278.1 mg, 1.31 mmol) and Pd(dppf)Cl2DCM (71.3 mg, 0.09 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH / ethyl acetate = 1 / 9) to give tert-butyl (S)-(1-(5-(4-(1-cyclohexylpiperidin-4- yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (90 mg, 35.5 % yield) as a yellow oil. LCMS (ESI) calc’d for C32H46N3O3S+ [M + H] + m / z 552.33, found 552. Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-cyclohexylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(5-(4-(1-cyclohexylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (90 mg, 0.16 mmol) in 4 mL EtOAc was added HCl(3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3- aminopyrrolidin-1-yl)(5-(4-(1-cyclohexylpiperidin-4-yl)phenyl)-3-methylthiophen-2- yl)methanone (Compound 179; 70 mg, 81.7 % yield) as a yellow solid. LCMS (ESI) calc’d for C27H38N3OS+ [M + H] + m / z 452.28, found 452.1H NMR (400 MHz, MeOD) δ 7.52 (d, J = 7.9 Hz, 2H), 7.25 (t, J = 7.4 Hz, 2H), 7.15 (s, 1H), 3.95 – 3.85 (m, 2H), 3.69 (ddt, J = 34.8, 14.9, 7.0 Hz, 4H), 3.51(d, J = 11.3 Hz, 2H), 3.14 (s, 13H), 2.85 (s, 1H), 2.35 (dd, J = 12.9, 6.1 Hz, 1H), 2.26 (s, 3H), 2.06 (dd, J = 18.0, 8.9 Hz, 7H), 1.90 – 1.82 (m, 2H), 1.64 (d, J =12.7 Hz, 1H), 1.47 (dd, J = 22.3, 11.4 Hz, 2H), 1.33 (dd, J = 25.5, 12.7 Hz, 2H), 1.15 (dd, J = 25.1, 12.3 Hz, 1H). EXAMPLE 41: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-cyclopentylpiperidin- 4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 180) Step 1 Synthesis of 4-(4-bromophenyl)-1-cyclopentylpiperidine To a solution of 4-(4-bromophenyl)piperidine (240 mg, 1 mmol) in DCM (10 mL) was added cyclopentanone (84.7 mg, 1 mmol), NaBH(OAc)3(317.7 mg, 1.5 mmol) and HOAc (60 mg, 1 mmol). The mixture was stirred at rt for 3h. The LCMS showed the reaction was completed and the desired product was found. The resulting mixture was washed with H2O (20 mL) and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(4- bromophenyl)-1-cyclopentylpiperidine (320 mg, 93.5 % yield) as a yellow oil. Step 2 Synthesis of 1-cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-cyclopentylpiperidine (320 mg, 1.04 mmol) in dioxane (10 mL) were added B2Pin2(263.6 mg, 1.04 mmol), KOAc (305.6 mg, 3.11 mmol) and Pd(dppf)Cl2DCM (169.4 mg, 0.2 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography EtOAc / MeOH=9:1 as eluent to give 1- cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (232 mg, 59.8 % yield) as a yellow oil. Step 3 Synthesis of tert-butyl (S)-(1-(5-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (250 mg, 0.64 mmol) in dioxane / H2O = 8:1 (18 mL) were added 1- cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (228 mg, 0.64 mmol), K3PO4(409 mg, 1.93 mmol) and Pd(dppf)Cl2DCM (104.8 mg, 0.13 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH / ethyl acetate = 1 / 9) to give tert-butyl (S)-(1-(5-(4-(1-cyclopentylpiperidin-4- yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (100 mg, 27.5 % yield) as a yellow oil. Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(5-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (100 mg, 0.19 mmol) in 4 mL EtOAc was added HCl(3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3- aminopyrrolidin-1-yl)(5-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3-methylthiophen-2- yl)methanone (Compound 180; 70 mg, 81.7 % yield) as a yellow solid. LCMS (ESI) calc’d for C26H36N3OS+ [M + H] + m / z 438.26, found 438.1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 4.06 – 3.98 (m, 2H), 3.91 – 3.79 (m, 2H), 3.74 (t, J = 11.8 Hz, 3H), 3.64 – 3.53 (m, 1H), 3.17 (t, J = 12.0 Hz, 2H), 2.97 (t, J = 12.1 Hz, 1H), 2.54 – 2.42 (m, 1H), 2.38 (s, 1H), 2.28 – 2.10 (m, 3H), 2.10 – 2.00 (m, 6H), 1.85(dd, J = 24.6, 6.2 Hz, 4H), 1.73 (d, J = 4.3 Hz, 2H). EXAMPLE 42: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-cyclobutylpiperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 181) Step 1 Synthesis of 4-(4-bromophenyl)-1-cyclobutylpiperidine To a solution of 4-(4-bromophenyl)piperidine(240 mg, 1 mmol) in DCM (10 mL) was added cyclobutanone (70 mg, 1 mmol), NaBH(OAc)3(317.7 mg, 1.5 mmol) and HOAc (60 mg, 1 mmol). The mixture was stirred at rt for 3 h. The LCMS showed the reaction was completed and the desired MS was found. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(4- bromophenyl)-1-cyclobutylpiperidine (290 mg, 93.7% yield) as a yellow solid. LCMS (ESI) calc’d for C15H21BrN+ [M + H] + m / z 294.09, found 294. Step 2 Synthesis of 1-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-cyclobutylpiperidine (290 mg, 0.98 mmol) in dioxane (10 mL) were added B2Pin2(250 mg, 0.98 mmol), KOAc (290 mg, 3 mmol) and Pd(dppf)Cl2DCM (160 mg, 0.19 mmol). The mixture was stirred at 100 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography EtOAc / MeOH=9:1 as eluent to give 1- cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (277 mg, 78.23 % yield) as a yellow solid. Step 3 Synthesis of tert-butyl (S)-(1-(5-(4-(1-cyclobutylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (300 mg, 0.77 mmol) in dioxane / H2O = 8:1 (18 mL) were added 1- cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (263 mg, 0.77 mmol), K3PO4(490 mg, 2.3 mmol) and Pd(dppf)Cl2DCM (125.8 mg, 0.15 mmol). The mixture was stirred at 95 ºC under N2for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 8) to give tert-butyl (S)-(1-(5-(4-(1-cyclobutylpiperidin-4- yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 47 % yield) as a yellow oil. LCMS (ESI) calc’d for C30H42N3O3S+ [M + H] + m / z 524.30, found 524. Step 4 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-cyclobutylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(5-(4-(1-cyclobutylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (200 mg, 0.38 mmol) in 4 mL EtOAc was added HCl (3 mL, 2M in EtOAc). The mixture was stirred at rt for 16 h. The LCMS showed the reaction was completed and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give (S)-(3- aminopyrrolidin-1-yl)(5-(4-(1-cyclobutylpiperidin-4-yl)phenyl)-3-methylthiophen-2- yl)methanone (Compound 181; 13.8 mg, 8 % yield) as a white solid. LCMS (ESI) calc’d for C25H34N3OS+ [M + H] + m / z 424.24, found 424.1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 8.3 Hz, 2H), 7.36 (t, J = 8.8 Hz, 2H), 7.27 (s, 1H), 4.00 (t, J = 7.3 Hz, 2H), 3.83 (ddt, J = 11.7, 5.9, 5.0 Hz, 2H), 3.76– 3.67 (m, 2H), 3.61 (d, J = 12.5 Hz, 2H), 3.01 – 2.87 (m, 3H), 2.53 – 2.42 (m, 2H), 2.38 (d, J = 4.7 Hz, 3H), 2.31 (dd, J = 15.7, 6.0 Hz, 2H), 2.15 (t, J = 13.4 Hz, 3H), 2.06 – 1.83 (m, 4H). EXAMPLE 43: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1- propylpiperidin-4-yl)phenyl)thiophen-2-yl)methanone (Compound 182) Step 1 Synthesis of 1-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-propylpiperidine (160 mg, 0.5669 mmol), B2Pin2(172.8 mg, 0.6802 mmol) and KOAc (166.9 mg, 1.7 mmol) in 5 mL 1,4-dioxane was added Pd(dppf)Cl2DCM, the mixture was stirred at 100ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 221 mg 1-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperidine as white solid. Step 2 Synthesis of tert-butyl (S)-(1-(3-methyl-5-(4-(1-propylpiperidin-4-yl)phenyl)thiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of 1-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine (172.6 mg, 0.524 mmol), tert-butyl N-((3S)-1-((5-bromo-3- methylthiophen-2-yl)carbonyl)pyrrolidin-3-yl)carbamate (170 mg, 0.4367 mmol) and K3PO4(278.1 mg, 1.3101 mmol) in dioxane / H2O (9 mL, v / v = 8:1) was added Pd(dppf)Cl2DCM (71.3 mg, 0.0873 mmol), the mixture was stirred at 95ºC under N2for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford 132 mg tert-butyl N-((3S)-1-((3-methyl-5-(4-(1- propylpiperidin-4-yl)phenyl)thiophen-2-yl)carbonyl)pyrrolidin-3-yl)carbamate as yellowish solid. Step 3 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-propylpiperidin-4- yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(3-methyl-5-(4-(1-propylpiperidin-4- yl)phenyl)thiophene-2-carbonyl)pyrrolidin-3-yl)carbamate(132 mg, 0.258 mmol) in 2 mL EtOAc was added HCl(4 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 12 h. After the reaction, the reaction was filtered, the filter cake was washed with EtOAc for 3 times to afford 34.5 mg (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(4-(1-propylpiperidin-4- yl)phenyl)thiophen-2-yl)methanone (Compound 182) as yellow solid. MS (ESI): mass calc’d. for C24H34N3OS 412.24, found 412 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 7.1 Hz, 2H), 7.34 (d, J = 7.1 Hz, 2H), 7.25 (s, 1H), 4.00 (d, J = 5.7 Hz, 2H), 3.81 (d, J = 17.4 Hz, 2H), 3.70 (d, J = 7.8 Hz, 3H), 3.13 (s, 4H), 3.00 - 2.92 (m, 1H), 2.47 – 2.43 (m, 1H), 2.36 (s, 3H), 2.16 – 2.01 (m, 5H), 1.84 (s, 1H), 1.05 (t, J = 6.5 Hz, 3H). EXAMPLE 44: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-isopropylpiperidin-4- yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 183) Step 1 Synthesis of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin-3- yl)carbamate To a solution of 5-bromo-3-methylthiophene-2-carboxylic acid (10.7 g, 48.4 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (9.02 g, 48.4 mmol) and DIEA (25.02 g, 193.6 mmol) in 150 mL DMF was added T3P (23.1 g, 72.6 mmol, 50 wt% in EtOAc), the mixture was stirred at 25ºC for 16 hours. After the reaction, the H2O was added and the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4and filtered, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl (S)-(1-(5-bromo-3-methylthiophene- 2-carbonyl)pyrrolidin-3-yl)carbamate (11.4 g, 60.5% yield) as a pale yellow solid. LCMS (ESI) calc’d for C15H22BrN2O3S [M + H]+ m / z 391.05, found 391.0. Step 2 Synthesis of 4-(4-bromophenyl)-1-isopropylpiperidine To a solution of 4-(4-bromophenyl)piperidine (10 g, 41.6 mmol) and 2-bromopropane (10.23 g, 83.2 mmol) in 100 mL MeCN was added K2CO3(17.25 g, 124.8 mmol), the mixture was stirred at 70 ºC for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography using petroleum ether / ethyl acetate = 7:3 ~ 1:1 as eluent to afford 4-(4-bromophenyl)-1-isopropylpiperidine (11.1 g, 93.51% yield) as a yellowish solid.1H NMR (400 MHz, CDCl3) δ 7.42 – 7.38 (m, 2H), 7.12 – 7.09 (m, 2H), 3.00 (d, J = 11.6 Hz, 1H), 2.77 - 2.72 (m, 1H), 2.48 - 2.40 (m, 1H), 2.23 (td, J = 11.6, 2.6 Hz, 1H), 1.84 – 1.68 (m, 4H), 1.08 (d, J = 6.6 Hz, 6H). Step 3 Synthesis of 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-isopropylpiperidine (10 g, 35.4 mmol), B2Pin2 (10.79 g, 42.48 mmol) and KOAc (10.42 g, 106.2 mmol) in 100 mL dioxane was added Pd(dppf)Cl2DCM (2.89 g, 3.54 mmol), the mixture was stirred at 100 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1 / 1 as eluent to afford 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (12 g, 97.74% yield) as a yellow solid. LCMS (ESI) calc’d for C20H33BNO2+ [M + H]+ m / z 330.25, found 330.2. Step 4 Synthesis of tert-butyl (S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate To a solution of tert-butyl (S)-(1-(5-bromo-3-methylthiophene-2-carbonyl)pyrrolidin- 3-yl)carbamate (10 g, 25.7 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)piperidine (10.16 g, 30.84 mmol) and K3PO4(16.37 g, 77.1 mmol) in 360 mL dioxane / H2O = 8:1 was added Pd(dppf)Cl2DCM (2.1 g, 2.57 mmol), the mixture was stirred at 95 ºC under N2for 16 hours. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography using ethyl acetate / MeCN = 3 / 7~1 / 0 as eluent to afford tert-butyl (S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (7.35 g, 54.47% yield) as a white solid. LCMS (ESI) calc’d for C29H42N3O3S+ [M + H]+ m / z 512.29, found 512.3. Step 5 Synthesis of (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- methylthiophen-2-yl)methanone To a solution of tert-butyl (S)-(1-(5-(4-(1-isopropylpiperidin-4-yl)phenyl)-3- methylthiophene-2-carbonyl)pyrrolidin-3-yl)carbamate (7.35 g, 14.4 mmol) in 100 mL EtOAc was added HCl (50 mL, 2M in EtOAc), the mixture was stirred at 25ºC for 16 hours. After the reaction, the mixture was filtered and the filtered cake was dissolved in pure water , which was dried through lyophilization to afford (S)-(3-aminopyrrolidin-1-yl)(5-(4-(1- isopropylpiperidin-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (Compound 183; 5.69 g, 94% yield) as a yellow solid. LCMS (ESI) calc’d for C24H34N3OS+ [M + H]+ m / z 412.24, found 412.3.1H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.24 (s, 1H), 4.02 – 3.98 (m, 2H), 3.89 - 3.82 (m, 1H), 3.80 - 3.69 (m, 2H), 3.58 – 3.55 (m, 3H), 3.25 – 3.18 (m, 2H), 2.99 – 2.91 (m, 1H), 2.50 - 2.41 (m, 1H), 2.35 (s, 3H), 2.19 – 2.12 (m, 5H), 1.42 (d, J = 6.7 Hz, 6H). EXAMPLE 45: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(3-methyl-5-(1,2,3,4- tetrahydroisoquinolin-7-yl)thiophen-2-yl)methanone (Compound 198) Step 1 Synthesis of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (500 mg, 2.3 mmol) and Et3N (1 mL, 7 mmol) in DCM (5 mL) was added Boc2O (617.4 mg, 2.83 mmol), the mixture was stirred at room temperature for 16 h. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford tert-butyl 7- bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg, 95.1% yield) as a colorless oil. Step 2 Synthesis of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-isoquinoline-2-carbox...

Claims

CLAIMS We claim:

1. A compound of Formula (I):or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: E is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E may be optionally substituted; E' is absent, or E' is C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and E' may be optionally substituted; and R3xand R4are each H or an independently selected optional substituent.

2. The compound of claim 1, wherein E' is absent.

3. A compound of Formula (II):or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CR14; L1is absent, or L1is C1-C6alkylene, C1-C6heteroalkylene, –O–, –S–, or –NR'–, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted; A is H, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, and A may be optionally substituted; or A and R11are taken together with the atoms to which they are attached to forman optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic ring; R11, R12, R13, and R14are each independently H or an optional substituent; each R' is H or C1-C6alkyl; and each of R3xand R4is independently H or an independently selected optional substituent, wherein no more than two of Z1, Z2, Z3and Z4are N.

4. A compound of Formula (II):or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CR14; L1is absent, or L1is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted by 1-4 independently substituents selected from =O (oxo), OH, and halogen; A is H, halo, C1-C10alkyl, C1-C10heteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, 5-6 membered heteroaryl, C6-C10carbocyclyl, or -5- 10 membered heterocyclic ring, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups; or A and R11are taken together with the atoms to which they are attached to form a C3-C7cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, wherein the heteroaryl and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein each of the rings is optionally substituted by one R1group and optionally substituted by 1-4 independently selected R2groups; each of R11, R12, R13, and R14is independently H or R3; R1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C9heteroalkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, or –L2–G, wherein the C1-C6alkyl may be optionallysubstituted with OH, and wherein the C1-C6heteroalkyl may be optionally substituted with C2-C6heteroalkynyl; L2is absent, or L2is C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, or -NR'-, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted by 1-4 substituents independently selected from =O (oxo), OH, and halogen; G is C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, or 5-10 membered heterocyclyl, wherein the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), OH, –NMe2, – NHMe, –NH2, CN, and halo; each R2is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), –OH, –NMe2, –NHMe, –NH2, and halo; each R3is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, cyano, and halo; R4is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, cyano, and halo; each R' is H or C1-C6alkyl; and R3xis selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo, wherein no more than two of Z1, Z2, Z3and Z4are N.

5. The compound of claim 3 or 4, wherein R3xis H or C1-C6alkyl.

6. The compound of claim 3 or 4, wherein R3xis H or –Me.

7. The compound of any one of claims 3 to 6, wherein R4is H, halo, C1-C6haloalkoxy, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, or C1-C6heteroalkyl.

8. The compound of any one of claims 3 to 7, wherein R4is H, –Cl, –Br, –OCF3, –Me, – OMe, –Et, –nPr, –iPr,–CH2OCH3, –CH=CH2, or –CH2CH=CH2.

9. The compound of any one of claims 3 to 8, wherein Z1is CR11, Z2is CR12, Z3is CR13, and Z4is CR14.

10. The compound of any one of claims 3 to 8, wherein Z1is N, Z2is CR12, Z3is CR13, and Z4is CR14.

11. The compound of any one of claims 3 to 8, wherein Z1is CR11, Z2is N, Z3is CR13, and Z4is CR14.

12. The compound of any one of claims 3 to 8, wherein Z1is N, Z2is CR12, Z3is N, and Z4is CR14.

13. The compound of any one of claims 3 to 8, wherein Z1is N, Z2is N, Z3is CR13, and Z4is CR14.

14. The compound of any one of claims 3 to 8, wherein Z1is CR11, Z2is N, Z3is CR13, and Z4is N.

15. The compound of any one of claims 3 to 14, wherein each of R11, R12, R13, and R14is independently H or R3, wherein each R3is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, and halo.

16. The compound of any one of claims 3 to 14, wherein each of R11, R12, R13, and R14is independently H or R3, wherein each R3is independently selected from the group consisting of –Me, –Et, –nPr, –iPr, –CF3, –OMe, –OCF3, –OH, –F, and –Cl.

17. The compound of any one of claims 3 to 16, wherein L1is absent.

18. The compound of any one of claims 3 to 16, wherein L1is C1-C6alkylene, C1-C6heteroalkylene, or –O–.

19. The compound of any one of claims 3 to 16, wherein L1is –CH2–, –OCH2–, – NHCH2–, –N(CH3)CH2–, or –O–.

20. The compound of any one of claims 3 to 19, wherein A is selected from the group consisting of halo, C1-C10alkyl, and C1-C10heteroalkyl, wherein the C1-C10alkyl and C1-C10heteroalkyl are optionally substituted by =O (oxo).

21. The compound of any one of claims 3 to 19, wherein A is selected from the group consisting of –F, –Cl, –Me, –Et, –nPr, –iPr,NHCH3, –N(CH3)2,22. The compound of any one of claims 4 to 19, wherein A is selected from the group consisting of C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, 5-6 membered heteroaryl, C6-C10carbocyclyl, and 5-10 membered heterocyclic ring, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups.

23. The compound of any one of claims 4 to 19, wherein A is selected from the group consisting of C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10aryl, and 5-6 membered heteroaryl, and A is substituted by one R1group and optionally substituted by 1-4 independently selected R2groups.

24. The compound of any one of claims 3 to 19, wherein A is selected from the group consisting of25. The compound of any one of claims 4 to 24, wherein each R2is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, =O (oxo), –OH, –NMe2, –NHMe, –NH2, and halo.

26. The compound of any one of claims 4 to 24, wherein each R2is independently selected from the group consisting of –Me, –Et, –nPr, –iPr, –CF3, –OMe, –OCF3, =O (oxo), – OH, –NMe2, –NHMe, –NH2, F, Cl, and Br.

27. The compound of any one of claims 4 to 24, wherein R1is H or –L2–G.

28. The compound of any one of claims 4 to 24, wherein R1is –L2–G.

29. The compound of any one of claims 4 to 28, wherein L2is absent.

30. The compound of any one of claims 4 to 28, wherein L2is selected from the group consisting of C1-C6alkylene, C1-C6heteroalkylene, and –O–.

31. The compound of any one of claims 4 to 28, wherein L2is –CH2–.

32. The compound of any one of claims 4 to 31, wherein G is C3-C7cycloalkyl or 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl has 1-3 ringheteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents.

33. The compound of any one of claims 4 to 31, wherein G is 3-7 membered heterocycloalkyl, wherein G may be optionally substituted by 1-4 RAsubstituents.

34. The compound of any one of claims 4 to 31, wherein G is selected from the group consisting of35. The compound of any one of claims 4 to 34, wherein each RAis independently C1-C6alkyl.

36. The compound of any one of claims 4 to 35, wherein G is selected from the group consisting of37. The compound of any one of claims 3 to 35, wherein A is selected from the group consisting of38. The compound of any one of claims 3 to 24, wherein A is selected from the group consisting of.

39. The compound of any one of claims 4 to 19, wherein A and R11are taken together with the atoms to which they are attached to form a C3-C7cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, wherein the 5-6 membered heteroaryl and 3-7 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, each of the rings optionally substituted by one R1group and optionally substituted by 1-4 independently selected R2groups.

40. The compound of any one of claims 3 to 19, whereinis selected from the group consisting of41. The compound of any one of claims 3 to 19, whereinis selected from the group consisting of,42. The compound of claim 3 or 4, wherein the compound is of Formula (IIa):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

43. The compound of claim 3 or 4, wherein the compound is of Formula (IIb):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

44. The compound of claim 3 or 4, wherein the compound is of Formula (IIc):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

45. The compound of claim 3 or 4, wherein the compound is of Formula (IId):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

46. A compound of Formula (III):or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: X1is NR1, O, S, SO2, CH2, or CHR1; X2is N or CH; R1is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, and –L2–G, wherein the C1-C6alkyl may be optionally substituted with one or more OH, and wherein the C1-C6heteroalkyl may be optionally substituted with C2-C6heteroalkynyl; L2is absent, or L2is selected from the group consisting of C1-C6alkylene, C1-C6heteroalkylene, -O-, -S-, and -NR'-, wherein the C1-C6alkylene and C1-C6heteroalkylene are optionally substituted by 1-4 substituents independently selected from the group consisting of =O (oxo), OH, and halogen; G is selected from the group consisting of C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, and 5-10 membered heterocyclyl, wherein the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, OH, CN, and halo; each R2is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, –NH2, and halo; each R3is independently selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, OH, cyano, and halo; R3xis selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; R4is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C9heteroalkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, cyano, and halo;each R' is H or C1-C6alkyl; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

47. A compound of Formula (III):or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: X1is selected from the group consisting of NR1, O, S, SO2, CH2, and CHR1; X2is N or CH; R1is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C1-C6haloalkyl, –NH2, and –G; G is selected from the group consisting of C3-C7cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyclyl, and 5-10 membered heterocyclyl, wherein the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and wherein G may be optionally substituted by 1-4 RAsubstituents; each RAis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, OH, CN, and halo; each R2is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and halo; each R3is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; R3xis selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; R4is selected from the group consisting of H, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, and halo; m is 0 or 1; n is 0 or 1;p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

48. The compound of claim 47, wherein the compound is of Formula (IIIa):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

49. The compound of any one of claims 46 to 48, wherein X1is NR1and X2is CH.

50. The compound of any one of claims 46 to 48, wherein X1is CH2or CHR1and X2is N.

51. The compound of any one of claims 46 to 48, wherein X1is NR1and X2is N.

52. The compound of any one of claims 46 to 51, wherein R1is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, OH, and halo.

53. The compound of any one of claims 46 to 51, wherein R1is selected from the group consisting of –Me, –Et, –nPr, –iPr, –OMe, –OCF3, –OH, –Cl, –F,54. The compound of any one of claims 46 to 53, wherein R3xis H or –Me.

55. The compound of any one of claims 46 to 53, wherein R3xis H.

56. The compound of any one of claims 46 to 55, wherein R4is –Me.

57. The compound of any one of claims 46 to 56, wherein m is 1 and n is 1.

58. The compound of any one of claims 46 to 56, wherein m is 0 and n is 1.

59. The compound of any one of claims 46 to 58, wherein p is 0.

60. The compound of any one of claims 46 to 59, wherein q is 0.

61. The compound of any one of claims 46 to 60, wherein the compound is of Formula (IIIb):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

62. The compound of any one of claims 46 to 60, wherein the compound is of Formula (IIIc):or stereoisomer and / or a pharmaceutically acceptable salt thereof.

63. The compound of any one of claims 46 to 60, wherein the compound is of Formula (IIId):or stereoisomer and / or a pharmaceutically acceptable salt thereof 64. The compound of any one of claims 46 to 60, wherein the compound is of Formula (IIIe):or a pharmaceutically acceptable salt thereof.

65. A compound of Formula (IV):or stereoisomer and / or a pharmaceutically acceptable salt thereof, wherein: Z1is N or CR11; Z2is N or CR12; Z3is N or CR13; Z4is N or CH; R11is selected from the group consisting of H, –OH, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy; R12is selected from the group consisting of H, –OH, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy; R13is H or halo; R14is selected from the group consisting of H, halo, C1-C6alkylene, C1-C6heteroalkylene, 5-7 membered aryl, 5-7 membered heteroaryl, and 3-7 membered heterocycloalkyl, wherein the R14may be optionally substituted with one or more R14a; R14ais selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C3-C7cycloalkyl, 5-7 membered aryl, 3-7 membered heterocycloalkyl, and –C(O)OR14b, wherein the C1-C6alkyl or the 3-7 membered heterocycloalkyl may be optionally substituted with one or more R14b; R14bis selected from the group consisting of –OH, oxo, C1-C6alkyl, C1-C8heteroalkyl, C2-C6alkynyl, and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl; wherein when Z2is CR12, R12and R14may be taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, or aryl, wherein the cycloalkyl or theheterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl; R3xis H or C1-C6alkyl; and R4is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C1-C6haloalkoxy.

66. The compound of claim 65, wherein Z1is CR11, Z2is CR12, Z3is CR13, and Z4is CH.

67. The compound of claim 65, wherein when Z1is N, Z2is CR12, Z3is CR13, and Z4is CH.

68. The compound of claim 65, wherein when Z2is N, Z1is CR11, Z3is CR13, and Z4is CH.

69. The compound of claim 65, wherein when Z2and Z3are N, Z1is CR11and Z4is CH.

70. The compound of claim 65, wherein when Z2and Z4are N, Z1is CR11and Z3is CR13.

71. The compound of claim 65, wherein R11is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy.

72. The compound of claim 65, wherein R12is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkoxy.

73. The compound of claim 71, wherein R11is selected from the group consisting of –Me, –Et, –Cl, –F, –OMe, and –OCF3.

74. The compound of claim 71, wherein R12is selected from the group consisting of –Me, –Et, –Cl, –F, –OMe, and –OCF3.

75. The compound of claim 71, wherein R11is –OH.

76. The compound of claim 71, wherein R12is –OH.

77. The compound of claim 65, wherein R13is halo.

78. The compound of claim 77, wherein R13is –Cl.

79. The compound of claim 65, wherein R14is selected from the group consisting of H, halo, C1-C3alkylene, C1-C6heteroalkylene, phenyl, 5 membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the C1-C3alkylene, C1-C6heteroalkylene, phenyl, 5 membered heteroaryl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more R14a.

80. The compound of claim 79, wherein R14is selected from the group consisting of –Et, –O–, –CH2–, –nPr, –iPr, –Cl, NHCH3, –N(CH3)2,wherein if R14contains a substitutable atom, that atom may be optionally substituted with one or more R14a.

81. The compound of claim 80, wherein R14is selected from the group consisting of –Et, –nPr, –iPr, –Cl, NHCH3, –N(CH3)2,82. The compound of claim 79, wherein R14is selected from the group consisting of83. The compound of claim 79, 80, or 82, wherein R14ais selected from the group consisting of C1-C3alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 6 membered aryl, and 4-6 membered heterocycloalkyl, wherein C1-C6heteroalkyl, C3-C7cycloalkyl, and 5-7 membered aryl may be optionally substituted with R14b.

84. The compound of claim 83, wherein R14ais selected from the group consisting of – Me, –Et, –CH2–, nPr,, wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b.

85. The compound of claim 84, wherein R14ais selected from the group consisting of – Me, –Et, nPr,, , , , , ,, , , , , , , ,wherein if R14acontains a substitutable atom, that atom may be optionally substituted with one or more R14b.

85. The compound of claim 79, 82, or 83, wherein R14ais selected from the group consisting of –C(O)OR14b,86. The compound of claim 79, 83, or 85, wherein R14bis selected from the group consisting of oxo, –OH, –Me, C3-C7heteroalkyl, C2-C3alkynyl, and 6 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl.

87. The compound of claim 86, wherein R14bis selected from the group consisting of oxo, –OH, –Me,wherein themay be optionally substituted with oxo or C1-C6alkyl.

88. The compound of claim 87, wherein R14bis selected from the group consisting of oxo, –OH, –Me, wherein themay be optionally substituted with –Me.

89. The compound of any one of claims 79-88, wherein when Z2is CR12, R12and R14may be taken together with the atoms to which they are attached to form an aryl, cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may be optionally substituted with one or more C1-C6alkyl or C1-C6heteroalkyl.

90. The compound of claim 89, wherein when Z2is CR12, R12and R14taken together are selected from the group consisting of91. The compound of claim 65, wherein R3xis C1-C6alkyl.

92. The compound of claim 91, wherein R3xis –Me.

93. The compound of claim 65, wherein R4is selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C1-C6haloalkoxy.

94. The compound of claim 93, wherein R4is selected from the group consisting of –Cl, – Br, –OCF3, –Me, –Et, –OMe,95. A compound selected from any compound set forth in Table 1, or stereoisomer and / or a pharmaceutically acceptable salt thereof.

96. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1 to 95.

97. A method of treating a subject with a neurodegenerative disease or disorder, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition of claim 96 or a compound of any one of claims 1 to 94.

98. The method of claim 97, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporaldementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler's disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay- Sachs disease, Schilder's disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), and autism, or any combination thereof.

99. The method of claim 97, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

100. The method of claim 97, wherein the neurodegenerative disease is Alzheimer's disease.

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